Ironic Narrative in A Farewell To Arms by Ernest Hemingway Essay

Within the pages of A Farewell to Arms, modernist work of the 1920s, Hemingway often blurs the lines between the romantic narrative pattern and the ironic one. Critics argue over the specifics of each case: Do his heroes change and grow? Do they stagnate? Do they fail? Are they initiated into some greater consciousness of the world around them? Are Hemingway’s heroes romantic conquistadors or are they ironic failures? How does an understanding of these heroes’ initiations enhance Hemingway’s meaning in the novel? These are the sorts of questions that must be considered in any effort to determine the necessity of an ironic reading of this important Hemingway work. Paradigms Romance and Irony Although tragedy and comedy have typified many movements and periods of literary history, for the purposes of this essay, it is necessary to focus upon the paradigms of romance and irony. These narrative patterns are not as familiar to many readers. Readers may associate romance with a particular genre of literature, whether gothic or harlequin, or recognize salient ironic details within plots, characters, and/or dialogues, but many fail to realize the archetypal patterns that define the literary paradigms of romance and irony and their relationship to one another. Foulke and Smith lay the foundation for this exploration of romantic hero versus ironic anti-hero and romantic quest versus anti-quest, yet this construction can be explored even more fully if one examines the elements of the hero’s journey as (de) constructed by Joseph Campbell in Hero with a Thousand Faces. In this work, Campbell draws from the traditions of Freud and Jung to illustrate how the â€Å"deeds of myth survive into modern times† (Campbell 4). Because themes of initiation and the related hero’s quest are fundamental to the human condition, tying into universal perceptions of birth, growth, and death, the quest theme itself is always a â€Å"shape-shifting yet marvelously consistent story† that fits into the psychologically prescribed â€Å"checkpoints† of a narrative pattern such as romance or irony (Campbell 3). In the realm of romance, young heroes, generally in possession of some power that transcends the ordinary, are called to adventure, initiated into some sort of knowledge or greater understanding of the universe (in other words, he or she receives the booty or treasure, whether physical, psychological, or spiritual), and returns transformed, armed with some sort of greater understanding about the world around him or her significant enough to improve the plight of humankind or at least improve the lot of society (Foulke and Smith 5). On the contrary, the ironic journey is rooted in, well, irony. Perhaps the ironic hero, plagued by a less than ordinary potency, living in a world of chaos and disorder, ventures upon an aimless journey, and either fails to attain the treasure, or perhaps even more significantly, remains unchanged by his or her quest (Foulke and Smith 5). The narrative modes of romance and irony, then, can best be explored by pitting one against the other. Each pattern illustrates or represents a polarized human experience: romance represents the imagined, idealized world of constancy and order, while the ironic mode represents â€Å"the world of frustrated human desires† (Foulke and Smith 8). Because of the universal significance of such patterns, such paradigms are powerful mechanisms for the exploration of the human condition. Ironic Narrative in A Farewell to Arms From the beginning of the novel, readers immediately sense the ambiguity and uncertainty of hero’s role in an unpredictable world. The book opens with an ironic tone depicting a wilting earth in a drenched autumn: â€Å"leaves all fell from the chestnut trees and the branches were bare,† even the vineyards are described as â€Å"thin and bare-branched† (Hemingway 4). And, even more poetically, Hemingway artfully sets up an ironic tone for the novel by cleverly, though morbidly, emphasizing that with â€Å"the winter came permanent rain and with the rain came the cholera†; though, â€Å"in the end† only seven thousand â€Å"died of it in the army† (Hemingway 4). With this opening, a wilting depiction of nature, Hemingway sets his readers up for an ironic interpretation of his novel. It is within the context of such a pervasive unsettling setting, as typical of the ironic mode, that readers encounter Hemingway’s ironic hero: Frederic Henry. Frederic is initially set into a traditional hero’s role: he is a soldier. And, not only is Frederic a soldier, but he is an American volunteer for the Italian army. Within the context of the traditional romanticized soldier hero, it could be suggested that such action as volunteering for someone else’s war is valiant, brave, and even representative of that larger-than-life archetypal hero depicted in narrative romance. However, Hemingway is certain to emphasize Frederic’s naivetà ©, if not foolishness, from the very beginning of this anti-hero’s journey. Although Frederic technically ranks as an officer, he describes his work to Catherine as â€Å"not really [with] the army,† but â€Å"only the ambulance† (Hemingway 18). As an ambulance driver on the Italian front, Frederic’s innocence is encapsulated in his belief that it is impossible for him to be killed at the front; after all, the war â€Å"did not have anything to do† with him (Hemingway 37). Frederic’s innocence is also depicted and reinforced by his obliviousness to the war; he is able to travel comfortably in convoy if in â€Å"the first car† and appreciate the â€Å"clear, fast and shallow† river and the mysterious looming mountains (Hemingway 44-5). Frederic’s ability to appreciate the â€Å"picturesque† Italian front illustrates his inability to realize the significance of both the â€Å"deep pools† of the river â€Å"blue like the sky† and the reality of life and death shuttled within his ambulance (Hemingway 47). This naivetà © is similarly reflected early in the novel by the fact that Frederic clearly and staunchly believes in the traditional virtues of soldiering: good soldiers are ‘†brave and have good discipline'† (Hemingway 48). When these naive character traits are coupled with the dominant impression presented by the fading, rainy fall, and cholera-struck winter, the stage is set early on in A Farewell to Arms for another Hemingway triumph of irony. However, from the beginning of the book, readers are aware that Frederic is becoming increasingly cognizant of the fact that â€Å"It evidently made no difference† whether he â€Å"was there to look after things or not† (Hemingway 16). When Frederic returns to the front after his leave time, he realizes that all is as he â€Å"had left it except that now it was spring† (Hemingway 10); the front had remained static, and neither side had advanced or taken new territory. As typical of the ironic hero, Frederic begins to think that perhaps â€Å"the whole thing† runs better without him anyway (Hemingway 16). From Frederic’s perspective, not even the wounded in the hospital are â€Å"real wounded†; rather, true casualties could only result from the action when the war picks back up again (Hemingway 12). Frederic’s dissatisfaction with the world around him represents his call to adventure. As a foreigner in someone else’s war, Frederic Henry is beginning to sense the calculated nature of war as well as his insignificance in this cataclysmic event. For regardless of the supposed honor of military service, Frederic is beginning to question the dignity of his post; he considers his position as an ambulance driver to be â€Å"not really the army,† the Italian salute, a gesture â€Å"not made for export,† begins to make him uncomfortable, and even the steel helmets soldiers are required to wear seem â€Å"too bloody theatrical† (Hemingway 18, 23, 28-9). And, even life at the front is beginning to grow dull: â€Å"The priest was good but dull. The officers were not good but dull. The King was good but dull.† Only the wine, â€Å"bad,† was â€Å"not dull† (Hemingway 38-9). Frederic is beginning to question his role, and his significanc e, within the context of the war, and within the context of his morality. All around Frederic Henry, soldiers much more connected than he is to the war, such as Italian peasants, workers, and citizens, recognize the horror of the war for what it is: senseless fighting for abstract principles that results in the death of innocent soldiers often blindly fighting for these goals. This reality is exemplified in Frederic’s encounter with a soldier suffering from a hernia at the front. The soldier, of course, wants out, but tells Frederic, the ambulance driver, that officers do not find his condition worthy of excusing him from duty. Henry advises the man with the hernia to â€Å"fall down by the road and get a bump on† his head so that he can legitimize taking the soldier to the hospital (Hemingway 35). However, irony permeates this situation. Henry and his compadres encounter the man with the â€Å"rupture† once again, only this time his head is bleeding as two men lift him; â€Å"They had come back for him after all† (Hemingway 36). This anecdote illustrates the fundamentally ironic nature of war: violence, injury, motivation, unpredictable motives and priorities, the inherent irony in fighting for someone else’s cause. Soldiers in war must struggle to choose to fight for arguably noble causes of an abstract nation, ideological principle, or political goal, look out for one another on the front, or simply prioritize their own survival. Frederic must grapple with why he is risking his life in this war at all. Is there more to fighting in a war than simply existing in a particular place at a particular time? Frederic himself suggests that he merely stumbled into the war: he â€Å"was in Italy†¦and spoke Italian† (Hemingway 22). How moral is it to participate in collective violence without a passionate code of ethics that supports the cause? These are the types of concerns plaguing Hemingway’s ironic hero as he is beckoned towards the threshold of adventure. Conclusion After analyzing the impotent nature of the major character of A Farwell to Arms, it becomes clear that the novel do indeed illustrate the futile struggle of a â€Å"lost generation.† Perhaps the most central question that must be explored in the consideration of whether or not this work are examples of the paradigm of narrative irony hinges upon the endings of the works. Does Frederic transform over the course of his literal and symbolic journey? It is clear that he does not. Frederic has learned that life is only meaningful if one lives it according to his or her own values, but he has also learned the lessons of the great irony: that â€Å"the world breaks everyone†¦It kills the good, and the very gentle, and the very brave impartially† and â€Å"The only thing that one can be sure of in this world is that one will be destroyed† (Hemingway 249; Phelan 54). Hemingway’s A Farewell to Arms ends in utter irony. When Frederic finally says goodbye to his beloved Catherine, he remarks that it is like â€Å"saying good-by to a statue.† The novel ends as Frederic walks â€Å"back to the hotel in the rain† (Hemingway 332). Left in a post-World War I experience, Frederic is lost, â€Å"bereft, homeless, and a drift† (Donaldson 15); Frederic Henry has learned the ironic lessons of life, and attempted to establish and live by a moral code dictated by his own creation, only to be defeated by the ultimate truth of existence, that is, that stripped of the traditional props of God, country, and tradition, the modern hero must face the â€Å"harsh and irremediable realities of existence† (Gurko 65). Hemingway’s skillful use of narrative irony in this text represents the most appropriate use of the modernist writer’s palette, for within the â€Å"anti-hero† of Frederic Henry readers find universal symbols for the plight of modern man. Because Hemingway stresses this fundamental futility of the human struggle within the confines of life and death, any interpretations that stress the romantic triumphs of this early Hemingway novel, that is, that this hero attain knowledge that can transform his world within his move from innocence to experience, is countered by the undeniable reality portrayed in this novel and that the book â€Å"end in overwhelming irony† (Smith 33). The ironic mode dominates as Frederic, desperate to add meaning to his life through love and experience, emerge as mere humans â€Å"clutching at a straw† (Smith 34). As Philip Young so eloquently argues in Hemingway: A Reconsideration, the fundamental reality of both the ironic mode, as well as Hemingway’s novel, is that â€Å"In the end, man is trapped† (93). Works Cited Campbell, Joseph. The Hero with a Thousand Faces. Princeton: Princeton University, 1968. Donaldson, Scott. Introduction. New Essays on A Farewell to Arms. Ed. Scott Donaldson. Cambridge: Cambridge University, 1990. 1-25. Foulke, Robert and Paul Smith. An Anatomy of Literature. New York: Harcourt Brace Jovanovich, 1972. Gurko, Leo. Ernest Hemingway and the Pursuit of Heroism. New York: Thomas Y. Crowell, 1968. Hemingway, Ernest. A Farewell to Arms. New York: Scribner, 1995 Phelan, James. â€Å"Distance, Voice, and Temporal Perspective in Frederic Henry’s Narration: Successes, Problems, and Paradox.† New Essays on A Farewell to Arms. Ed. Scott Donaldson. Cambridge: Cambridge University, 1990. 53-74. Smith, Paul. â€Å"The Trying-out of A Farewell to Arms.† New Essays on A Farewell to Arms. Ed. Scott Donaldson. Cambridge: Cambridge University, 1990. 27-54.

Economics article commentary: June Harvest to Reduce inflation Essay

Inflation refers to a persistent rise in the general price level in a given period of time usually one year. There are two main types of inflation namely, demand pull inflation and cost push. Demand pull inflation is caused by raising aggregate demand that pulls up prices in the economy. There are several factors that cause this type of inflation, for example, when government reduces income tax leaving consumers with more disposable incomes to spend. However, as far as this article is concerned it is basically cost push inflation that is of major concern. Cost push inflation is caused by rising costs of production that forces producers to increase prices of the final products. High food prices have been the main driver of inflation due to the drought that hit the country early last year. Agriculture depends on natural factors beyond human control such as weather. A drought will cause shortages that will result in escalating prices as shown in the diagram below. Figure 1 DD and S1S1 are the original demand and supply curve respectively. A drought will cause a shortage that will make the supply curve to shift to the left, that is, to S2S2 and price to rise from P1 to P2 as quantity decreases from Q1 to Q2. When the drought affects most parts of the country then aggregate supply of food will fall. This inevitably makes food prices to rise. Furthermore, the article says that the rise in inflation has also been due to increase in international crude oil prices that have resulted into increases in the pump prices of fuel. Fuel is a major component in the production process and so any increase in its price will increase production costs. Consequently, there would be a fall in short-run aggregate supply as shown in the diagram below. Figure 2 AD and SRAS1 are the aggregate demand and short-run aggregate supply curves respectively. A rise in cost of production shift the SRAS curve to the left that is, to SRAS2 average price increases from P1 to P2. Although inflation benefits sellers in terms of increased revenue, on the whole, it has several adverse effects. Some of these include reducing the living standard of especially fixed income earners, such as pensioners and salaried workers. This is especially since the article mentions that ‘the cost of living has been on an upward trend following increases in inflation that reached to 14.1%’. So anything that can help to reduce inflation is a welcome move. The title of this article â€Å"June Harvest to reduce inflation†¦Ã¢â‚¬  shows that relief is on the way. Reducing Inflation means that prices will fall making essential commodities affordable by the vast majority of the consumers. However, before the harvest brings the relief the government has a number of policies at its disposal that it may use to combat inflation. Government could use monetary and fiscal policies. For instance in the case of fiscal policies the government could increase income tax to reduce disposable income of consumers. This helps to reduce aggregate demand and so stabilizes prices. The problem with this policy is that it makes the government unpopular among the voters electorate. Furthermore, it may serve to worsen the unemployment problem and might also through down the economic growth in the long run. Government could also use the supply side policies. These are policies that are used by government to increase the supply potential of the economy. For example, the government could abolish minimum wage laws. This would make it cheap to employ workers but would also reduce total cost of production. Its disadvantage is that workers are bound to be exploited by their employers. In conclusion, government of Uganda should put in place a mechanism to prevent future shortage of food by operating buffer stock schemes. And although such schemes have problem, such as cost of shortage, but their existence helps to ease shortages of foodstuffs caused by unpredictable climate changes. After all, ‘prevention is better than cure’. This is important also because the government of Uganda has no control over the international crude oil prices.

Proctor and Elizabeth Relationship

‘The Crucible’ is a novel which was written by Arthur Miller in 1953. It takes place during the times of the Salem witch trials in Massachusetts. This was a time of much hypocrisy in the people of the town of Salem. Many people believed anything they heard or saw. Although The Crucible is fictitious, the story depicts the historical information of the Salem witch trials, and blends them with fictitious characters to create a very realistic plot and conflict in the story. Miller wrote this play as a response to the political environment in which he lived. The story relates to the McCarthy trials. During the 1950's Senator Joseph McCarthy accused many American leaders of being communists. This lead to many accusations that people were communists. Some people believed him because they had fear of communism. McCarthy was, in effect, conducting â€Å"witch hunts†. The Red Scare was a witch hunt where the US government was searching for â€Å"dangerous communists. † Accusations came from left and right, much the same as the characters did for â€Å"real witches† in The Crucible. This meant that people were forced to either confess to the crime of witchery or shove the blame towards a different person. As an effect of this bias, the accused were never discharged, but were given the opportunity to confess to the crime of witchcraft to lessen their sentence. With the red scare, the accused were given a chance to give up names of other suspected communists to lessen their sentence as well. In both situations, there were people who confessed even though they had no relation to the crime at all. The majority, however, valued their morals and refused to give into political pressure by lying. This is shown as abuse of power. The puritans were a group of English Protestants in the 16th and 17th century. The entire plot of the novel is moulded by the repressive Puritan society. Like many puritan women, Elizabeth Proctor is dutiful and loves her husband dearly. Yet, Elizabeth is hurt by the fact that her husband was having an affair with their â€Å"strikingly beautiful† young servant (Abigail). She finds it hard to show emotion and this affects her relationship with John Proctor vastly. In Act One we can see that there is ‘heat’ and ‘passion’ between John and Elizabeth. When Abigail says, ‘I know how you clutched my back behind your house and sweated like a stallion whenever I come near! ’ She's saying that John still lusts after her, breaking into a sweat when he sees her. She's holding the affair over his head and reminding him how he has sinned would like to sin again. We can see that Abigail has real feelings for John and they have a sexual attraction between them. With Abigail being a 17 year old puritan girl and John being a married man, this is clearly outrageous and shows that he was prepared to break his rules. Proctor convinced himself he was a sinful man that had done wrong, and to have respect for himself once again, he must break off all ties with Abigail. When Abigail mentioned to Proctor the relationship she and he once had, he said to her, â€Å"No, no, Abby. That's done with,† and, â€Å"Abby, you'll put it out of mind. I'll not be comin' for you more. Even when Abigail tried to persuade Proctor to admit his love for her, he still denied it and claimed he had no love for her any longer. In all of Abigail's persuasion to try to get him to admit his love for her, Proctor replied, â€Å"Abby, I may think of you softly from time to time. But I will cut off my hand before I'll ever reach for you again. Wipe it out of mind. We never touched, Abby. † Proctor saying to Abigail that they never touched was his way of trying to get through to her that the relationship between the both of them had to end here. In Proctor's mind, saying that to Abigail was a finalization of their affair and gave him the closure that he needed to truly forget what he and Abigail had between them. The affair between Proctor and Abigail also had made his love for Elizabeth grow stronger. The guilt of the affair made him realize how Elizabeth was a good woman and deserved more than a cheating husband, and he refused to allow Abigail to speak wickedly about her. Abigail said bitterly to Proctor, â€Å"Oh, I marvel how such a strong man may let such a sickly wife be -,† in which he interrupted angrily with, â€Å"You'll speak nothin' of Elizabeth! Abigail, realising the respect he now had for Elizabeth as to not let her speak of Elizabeth in such a manner, then tried to convince Proctor otherwise, saying, â€Å"She is blackening my name in the village! She is telling lies about me! She is a cold, snivelling woman†¦ † Elizabeth is shown as a ‘cold’ woman whereas Abigail and Proctor have ‘heat’ – ‘no wintry man’. The anger he felt at this time was not only towards Abigail, but also towards himself. He felt he had sinned greatly and did not provide Elizabeth, a mother of three children, with the respect and loyalty that one would expect out of a husband.

Financial Management Principles Essay Example | Topics and Well Written Essays - 1000 words

Financial Management Principles - Essay Example Net profit margin of the company further reveals that the company is remained with only about 7% of the total sales revenue after meeting cost of sales, operating expenses, interest expense, taxes and dividends etc. The difference between the company’s gross and net profit margin indicate the amount of profit foregone in the course of meeting various expenses. This means that the company has lost about 93% of its revenue in meeting all the various expenses. The return on assets ratio for the company in consideration is 4.88%, which connote that the company has utilized all of its various fixed and current assets to generate a return of 4.88% after meeting all the expenses. Strident Marks Inc.’s return on equity ratio reveals that the company has been able to generate a profit of 8.49% after engaging the total funds invested by its investors and shareholders for the year ended 2005. The current ratio for Strident Marks Inc. reflects that the company has a pretty healthy state of liquidity, i.e., it keeps about $2.57 worth of current assets to pay off $1 worth of current liabilities. The company’s working capital position is highly satisfactory and its current assets are greatly sufficient to meet its current liabilities. However, having such a high current ratio also reveals that some of the company’s fund is lying idle without being invested into the business. The quick ratio for the company shows that after keeping aside inventory from the current assets, the company is left with $2.48 worth of assets per $1 worth of liabilities. It also shows that not much of the company’s cash is tied up into inventory and the company’s short-term position is highly liquid. This ratio reveals that 34.68% of the company’s total assets are financed with borrowed capital, while rest of the assets are financed with equity funds supposedly. Hence the company currently banks on less external debts

Case Problems Involving the First Amendment Essay

Case Problems Involving the First Amendment - Essay Example The law gives the United Striates Government the right to release information or refuse to release and grants nine exemptions, which can be applied to stop disclosure of sensitive information (Russomanno 147). When stopping the publication the judge may use the theory of interpretation of the first Amendment Act on the Freedom of speech that deals with content regulation. This states that the government has the right to bar any publisher publishing information that may be viewed as threatening national security. In an example the case of Miami Herald Publishing Co. v. Tornillo, the court found that at times it is important for the federal government to bar release of information that may threaten the national security. When the judge is making the ruling on this case there are several things, he will have to put into consideration. The first one is the perceived effect on national security the release of the report would have and the other is the right of the press to publish information. He will look to see if the press freedom being infringed and if so will allow the information be published. On the other hand, if the information is proven vital and threatening national security he will bar it from being

Significance of Community College Faculty Development Programs Research Paper

Significance of Community College Faculty Development Programs - Research Paper Example Such is the philosophy behind faculty development. Colleges and universities encourage their faculty to engage in studies so they are well-equipped with the knowledge and skills to teach their students, who are mostly young adults who just graduated from high school, or even older adults who choose to keep on pursuing further studies. This paper aims to review, critique, and highlight the practical, and the scholarly significance of faculty development. Specifically, the review documents how faculty development impacts the duties, responsibilities and assigned tasks of faculty members, specifically in two-year colleges. II. Definition of Faculty Development In reviewing the literature, various definitions of faculty development are offered. One is by Nelson (1983): â€Å"Faculty development is any activity that is â€Å"designed to improve faculty performance in all aspects of their professional lives – as scholars, advisers, academic leaders, and contributors to institution al decisions† (p. 70). This definition identifies the roles that the faculty members take on when they assume their positions in their college or university. The roles enumerated reflect heavy responsibilities that require intelligence and skill. Sullivan (1983) agrees with Nelson’s definition in claiming faculty development’s concern in advancing the knowledge in one’s subject matter and mastering one’s own craft as it relates to teaching. Elbe & McKeachie (1985) follow suit in identifying faculty development as â€Å"college and university activities that are designed to "help faculty members improve their competence as teachers and scholars" (p. 35). These definitions point out to improving professional skills of the faculty, but on a more personal note, Rostek... This research illustrates that in reviewing the literature, various definitions of faculty development are offered. One is by Nelson: â€Å"Faculty development is any activity that is â€Å"designed to improve faculty performance in all aspects of their professional lives – as scholars, advisers, academic leaders, and contributors to institutional decisions†. This definition identifies the roles that the faculty members take on when they assume their positions in their college or university. The roles enumerated reflect heavy responsibilities that require intelligence and skill. Sullivan agrees with Nelson’s definition in claiming faculty development’s concern in advancing the knowledge in one’s subject matter and mastering one’s own craft as it relates to teaching. Elbe & McKeachie follow suit in identifying faculty development as â€Å"college and university activities that are designed to "help faculty members improve their competence as teachers and scholars". These definitions point out to improving professional skills of the faculty, but on a more personal note, Rostek & Kadivko add that the faculty’s professional development should include "purposeful learning experiences undertaken in response to individual needs". On a more collective scale, Centra defines faculty development as â€Å"college and university activities that are designed to "renew and maintain vitality of their staff†. Trends and issues in education develop in both breadth and depth. This process is faster due to technology and emerging modes of communication.

Aircraft Materials and Hardware Essay Example | Topics and Well Written Essays - 2500 words

Aircraft Materials and Hardware - Essay Example This, thus imply that race was the main subject under scrutiny. In this respect, the researcher showed that only AA children displayed association between cardiovascular regulation, BMI growth, and childhood obesity. As much as the researcher conclusively showed that poor cardiovascular regulations can be a serious risk factor for the development of obesity, the complete mechanism of this link could not be assessed by this study (Graziano et al., 2011). It is therefore prudent to set up a research that investigate if there was an association between obesity and cardiovascular diseases among children within the age range five to ten but not limited to African American children. It is also evidenced from the literature so far explored that there is lacking research to ascertain if age is a factor as far as childhood obesity cases are concerned. Clearly, most researchers tend to focus on other factors as gender, and genetics providing little information on how different age groups among children differed significantly or not. For instance, it is cited that Childhood obesity is increasing at the alarming rate worldwide with America alone having 17% obese children and adolescent between the age of 2 and 19. This studies show that although genetic compositions are still regarded as major contributor, obesity among children has almost doubled in recent years indicating change in lifestyle as an important reason. In another separate study, which used a minimum of 30 students from 134 high schools of America, the study population was classified according to region, size, ethnicity, and curriculum. This study evaluated the influence of physical activities, sedentary activities, and dietary habits on AA childhood obesity. Results, as recorded by Dodor et al. (2010) in this article, state that low physical activities and high sedentary lifestyle increase body weight and obesity in the adolescents. Also, greater intake of fruits and vegetable reduce obesity. However, this s tudy did not establish any relation between different age groups children in relation to obesity. One or two statements concerning age as a factor were mentioned however, there is no detailed study that focused on age as a dominant factor among children. This paper thus, proposes a research to be conducted to ascertain if obesity significantly changes as children transform from toddlers to adolescence. In the proposed study seeking to ascertain if there existed an association between obesity and cardiovascular diseases among children within the age range five to ten but not limited to African American children, the researcher should employ a quantitative research

Motivational Needs Essay Example | Topics and Well Written Essays - 500 words

Motivational Needs - Essay Example This includes food, sleep, water, exercise, clothing shelter and so forth (Iigo, 2000). Coon (2000) stated the three major categories of motives. Primary motives- which are based on biological needs that must be met for survival. The most important primary motives are hunger, thirst, pain avoidance, and needs for air, sleep, elimination of wastes, and regulation of body temperature. Love and Belongingness Needs. When the individual has minimum satisfaction of his survival and security needs, belongingness needs become important to him. The need for love, acceptance and approval by others - his family, friends those with whom he works (Cawaon, 1999). Cognitive Needs. We live in a decade where the source of power is information and education. Never in the lifetime of man has learning resources exploded and expanded to a phenomenal degree as today. Knowledge is everywhere and technology is facilitating our means of getting to it and using it (Puangco, 2005). Bandala et al. (1996) students motivation in general is high although students achievement motivation had a higher degree of motivation than the other areas. This suggests that students are continually striving, changing and trying to achieve their goals in life.

Tablet Devices and Comfort Essay Example | Topics and Well Written Essays - 1250 words

Tablet Devices and Comfort - Essay Example We have the slate tablet which is also referred to as the iPad.It has a touchscreen unit which and does not have a keyboard. Lastly, there is the rugged tablet that can stand all the rough handling by the students. They have hard drives that are usually shock protected. Some people argue that the tablet devices should replace the books that learners use in their classrooms. Using the tablets may have various disadvantages to the learners like the costs. Some of them are expensive and not each parent can afford to buy for their children. Background The tablet devices may have their advantages but some people choose to be against it. In the world today, the education system has been in the recent years become technological. Many learners now are able to use computers at school and at home. Looking at the question of using the traditional books that almost all the schools use, some parents and most students find it very hectic to move around carrying bags to schools. Some of the bags ar e very heavy and may cause the students to acquire diseases of the lower back. Both the books and the tablet devices have their advantages and the disadvantages. From the kindergarten to most universities in the world today, tablet devices are playing the biggest role in the education system.  Ã‚   The tablets may enhance their urge for going to school. With the use of tablets in schools, students are able to prepare themselves for the 21st-century workforce which uses the tablets for the smooth running of their work. Tablet devices may be seen as very costly as compared to the traditional books. Other than that, they have advantages to the parents and the learners. First of all, the tablet devices have apps. The apps are important and very efficient because whether the device is pointed to the sky or elsewhere, the educational apps make learning fun for many kids especially those in the elementary level. In the classroom settings, the use of the apps can be used by tutors who will give the learners the curiosity to learn more. The apps are used as a research tool for all the students especially in colleges (Jarrett and Su 25). If one compares the tablets and the traditional books, it is evident that the books are not very interesting and many learners don’t find it very interesting to use them in a classroom setting. Secondly, the tablet devices bring about interactiveness among the learners and all the teachers. The uses of the tablets that were used in the 20th century like the computers have video games that mostly bring the learners together. As a result of this, they learn and most of them think very differently. For a classroom to have the very interactive lesson, they need to have tablets which engage the students and thus giving them interactive experiences. These experiences cannot be found when the students just use books in the class. The tutor needs to have outside class activities in order for them to interact with the students.

Discuss the uses of recombinant DNA technology with respect to Essay

Discuss the uses of recombinant DNA technology with respect to medicine - Essay Example From a medical viewpoint, recombinant DNA technology can have immense potential. For example, many diseases are caused by the lack of certain genes or faulty protein production which leads to impaired functioning of important biochemical pathways. By using recombinant DNA technology to complement those defects and producing the lacking protein it is possible to effectively treat these diseases. An extremely successful example of this particular use is the case of insulin production for the treatment of diabetes. Previously, insulin for treatment used to be isolated from bovine sources, by extracting the pancreatic tissue and purifying insulin from here. However, two major problems are immediately obvious: first, this is extremely labor-intensive, yields are low and therefore it becomes expensive and quantities are limiting, thus treatment becomes an expensive option. Second, due to the exquisite specificity of our immune systems, the bovine protein is immediately differentiated from the human and this could lead to rejection by our immune system. Recombinant DNA using the human gene would solve this problem as the gene and therefore protein would be the human variety and would not be rejected. Second, since cloning is most often done in bacteria which have short doubling times, the massive amplification of the gene and therefore the protein leads to cheaper bulk production and lowers costs. Insulin therefore has become far more available for treatment with the advent of recombinant DNA technology. Growth hormone has also been successfully used this way. Another application of this technology is in the production of vaccines. Historically, the identification of antigens and the production of vaccines against them has been a laborious task. It involved purifying various protein components from viruses or bacteria after culturing them, and testing them in animal subjects to determine their antigenicity. The major problems there were, first, the difficulty in purifying those microbial toxins due to contamination, low concentrations etc., and furthermore, viruses and certain bacteria, like Mycobacterium, are obligate parasites and cannot be grown in vitro cultures in order to purify their components. By cloning their genes via PCR amplification and cloning into bacterial expression hosts, we can circumvent these issues and skip past the rate-limiting step of purification since cloning produces proteins in bulk. This strategy has been used with some success for many viruses, including the HBV virus. (Medscape). However this is not without its own problems when one looks at the evolution of viral antigens and the rate of mutation and development of new strains. Nevertheless DNA technology has speeded up the development of vaccines to a point where we now hold a sporting chance against these diseases. The technology is also used in the field of diagnostics. PCR and other DNA technology techniques are used to determine if people are carriers of cystic fibrosis genes, Huntington's disease gene and to help in gene therapy for these diseases. PCR and DNA

An essay considering whether Romeo and Juliet Essay Example for Free

An essay considering whether Romeo and Juliet Essay Romeo and Juliet was a play written by William Shakespeare in 1595. William Shakespeare died on St. Georges day, 23rd April, 1616, making Romeo and Juliet one of his earlier plays; written in what is now described as his second period, from his joining the Lord Chamberlains men in 1594 to the opening of the Globe Theatre in 1599. The diversity of Shakespeares work included comedies, histories and tragedies as well as poetry. Romeo and Juliet comes under the category of a tragedy, tragedy meaning an event in which something dreadful occurs, or in a theatrical sense a serious play with a tragic theme, often involving a heroic struggle and the downfall of the main character. This definition of tragedy relates to Romeo and Juliet because it is a play in which both the principal characters die in preventable circumstances at the close of the play. The downfall of Romeo and Juliet occurs by the fact that both characters start as young, beautiful descendents of powerful families and find themselves fleeing the city of Verona in fear of their lives and their relationship both banished by the authorities or their own households. However, an alternative view could be developed by looking at the perception of the word tragedy when the play was written; in the late 16th century. People of the time were of the view that if something tragic were to happen it must happen to a person of innocence, otherwise it is not technically tragic. Romeo is not an innocent person because he takes the life of another person on more that one occasion, with the murders of Tybalt and Paris. Even though there is the argument that these crimes were a consequence of his obsessive and at times over-enthusiastic love for Juliet, they are still actions that take away his virtuousness. Juliet damages her purity by treating the wishes and guidance of her parents with contempt and disregarding the arranged marriage to Paris. These egocentric actions help develop another, more imperfect impression of the two protagonists which provides an argument against Romeo and Juliet being a tragic play. In further illustration, tragic storylines generally end in unhappy circumstances, which on the one hand Romeo and Juliet does with the many deaths, for never was a story of more woe, than this of Juliet and her Romeo. Whilst on the other hand it could be argued that a more exultant conclusion occurs by the fact that the long-standing feud between the Montagues and the Capulets is finally resolved through their deaths. Basis for this statement is provided in the final scene by Capulet, O brother Montague, give me thy hand, this is my daughters jointure, for no more can I demand. In Shakespearean times Romeo and Juliet would have been compared to such tragic plays as Hamlet and Macbeth which were tragedies to the exact definition because they entailed stories of monarchs with flawed characters diminishing from the highest place in society to death over the course of the play. These stories fulfilled the public criteria for a tragic tale; a concept initially introduced by Aristotle, a Greek philosopher who lived from 384 to 382 BC. He produced directives for the perfect tragedy, concepts which heavily influenced academics and writers throughout Europe. He dictated that, the tragic heroes of any play must be people of royal or other high-born backgrounds. Therefore, Romeo and Juliet can be argued against being a tragedy because the two central characters are not royalty or part of any particular hierarchy. Many contend that being young and beautiful puts them in a social position to surpass most to begin with, although this does not fit unerringly into Aristotles theory. Aristotle exactly specifies the protagonists must be of royal or other high-born backgrounds, explicitly kings or generals, which Romeo and Juliet are not. The aforementioned statement can be supported by the following quotation from act three, scene one, in which Romeos killing of Tybalt is analysed, with the prince announcing, Immediately we do exile him hence. The fact that he has been exiled prior to his death illustrates further the fact that he is at a low point in society. Additionally, Aristotle also expresses his belief that these high born protagonists should have fatal flaws which lead to their downfall. Romeos fatal flaw is his impetuous and spontaneous nature which causes him to act before thoroughly thinking about what he is doing and considering the consequences of his actions. An example of his rashness comes when Balthasar tells Romeo that Juliet is dead, not knowing it is a faked death, hire post-horses, I will hence to-night. Here he is saying he will return to Verona, which he has been banished from, without waiting for news from Friar Lawrence; an action, as the audience soon finds out, that causes his death. His hot-headed rashness develops into the fuel for his uncontrollable obsession for his love, Juliet; who herself is fatally flawed by her notorious and narcissistic disobedience which causes her to defy the instructions and beliefs of her family. Juliet becomes so caught up in the irrepressible ardour of her relationship with Romeo that she fails to see the outrage and hatred she is rousing from an already hostile feud between two households. An example of her defiance comes when her mother tells her of her arranged marriage to Paris, He shall not make me there a joyful bride. Here she refuses to marry Paris, which infuriates her parents, causing them to reject their daughter; and inevitably her characters downfall as she is now shamed. These self-centred actions defiantly caused their demise leading to their death because if they both were to act with less haste when fuelling their love for each other then some of the consequences that occurred may have been prevented. Therefore, it is possible to maintain that Romeo and Juliet both suffered dramatic downfalls due to their own actions. On the contrary to this it could also be argued that as both their families recognised their lives by erecting statues of them, for I will raise her statue in pure gold, their characters therefore living on in a manner of speaking, meaning that their characters were not entirely degraded by their actions, thus rendering their characters not downfallen. Moreover, another notion primarily introduced by Aristotle was centred around the audiences perception of a tragedy, and how this could be used to define a tragic play. He said that the audience should feel pity and terror, pity for the hero and terror at the importance of the gods. This relates to Romeo and Juliet in the sense that the heroic characters are Romeo and Juliet themselves, whom the audience does feel a certain amount of pity for because of the unfortunate and seemingly preventable misfortunes that happen to them throughout the course of the play. Juliet is pitied for the fact that she is disowned by her family, do as thou wilt, for I have done with thee.

William Blake- subject, language and form Essay Example for Free

William Blake- subject, language and form Essay Blakes poems put forward a powerful social message which reflects the time in which he was writing. With reference to at least five of his poems, show how Blake achieves this through his use of subject, language and form In this essay I will be analysing five of Blakes poems which are A Poison Tree, The Chimney-Sweeper (experience), The Chimney-Sweeper (innocence) London and The Human Abstract. Each of Blakes poems has a powerful social message, and my aim is to analyse the message he is trying to portray through these poems. The subject, language and form his poems uphold are some of the main devices that help put forward his opinion at his present time, the 18th century. The powerful social message Blake was trying to convey to his readers was human suffering during his era, he showed this through his poems which marks his sympathy. At this day and age modern readers understand Blake as a writer and see the message he is trying to put forth through his poems. Although in his time, Blake was considered very strange. Born in 1757 into a Christian but non conformist London family, most of his life he spent in London. In 1783 he published his first volume of poems. Many changes were taking place in Blakes society, between 1750 and 1850, late 18th century the industrial revolution was changing the society through huge revolutions in technology in England. England changed from a rural population made from agriculture to a manufacturing society consisting of factories. Oppression of women and children was apparent so they worked for lower wages. Employment laws did not exist yet, some may have had to work up to 14 hour days with low wages. Now a days, these things are seen as wrong, throughout the 18th-19th century employing children and women with low wages and others with ridiculously long hours was seen as normal and no action was taken against it by either the establishment, monarchy or church, this caused Blake to be against all establishments which did not try and help the problems 18th century England was facing. Blake, being the rare few of many in England, became aware of these faults. His views were similar to our contemporary day. Many writers were moved by the industrial revolution. They felt it was important to shine light on the poor conditions of the working class and use of child labour. This change changed the attitudes of those living in England, many rich well off people became ignorant towards the conditions many poor, lower class, people were facing. The attitude of many high class people was apparent as growth and human spirit was not possible under conditions of social oppression. Also the establishment did nothing about the poor working conditions. In the 18th century poetry was used to spread news about life in general. Blake made a lot of reference to the bible in most of the poems he wrote. In his poems his ideas are powerful and convincing. Blake did not agree with political radicalism, he was strongly anti-establishment (government monarchy). He believed everyone should be as a liberating force. The need of individual imagination was important to Blake and the feeling above reason. He had love of nature and the natural, referring to the world before the industrial revolution, especially in reflecting the spirituality of things. He was against the church as it was an establishment and did nothing about the poor conditions many endured but he was for the religion of Christianity as it is strongly portrayed through his poems with the constant reference to biblical terms. The bible was most easily accessible to Blake as he was self taught. Chimney sweeping was not seen as wrong as child labour was not morally wrong. Blake wanted to show his feelings towards this wrong way of labour. In the 18th century the church did nothing about this cruel situation where children were being treated like slaves. The church let this cruelty act go on, the words of the church were being voiced through the chimney sweeping children. The poem called The Chimney-Sweeper innocence is about a young boy being sold, by his father, into the recruiting of young children to clean chimneys. A boy, the narrator, in this poem is so innocent he doesnt know any better and does not see it as wrong. The father is selling the boy for money, as it mustve been scarce for most dealing with the new ways of the revolution. In this poem Blake is trying to emphasise child labour and uses it from a childs perspective to evoke emotion out of the reader as the reader would more likely feel sorry for a child. His innocence is apparent in the first stanza as in the first verse it is written that the boy is not articulate while yet my tongue could scarcely cry. The boy is unable to pronounce sweep and instead pronounces weep yet again showing his innocence and intensifies his youth. The reader is directly address when it says so your chimney I sweep This triggers guilt in the reader, knowing such a young boy, unable to even pronounce sweep, is cleaning your chimney. At the end of stanza one alliteration is present sweep and in soot o sleep the pronunciation of s shows his progress. In stanza 2 the narrator refers to his friend Theres little Tom Dacre, who cried This gives off the persona of a child as children talk about a friend to put across their feelings on that person. That curled like a lambs back a lamb is a symbol of sacrifice in a biblical sense. Tom is sacrificing himself to cleaning the chimneys this is represented by him having his head shaved. A very vivid image is mentioned in stanza three it talks about Tom having a night mare about his many friends locked up in coffins of black the picture being painted in your mind is relating to the black, also meaning fear and dark, chimneys the boys have to climb and clean. It is suggesting that the sweeping of the chimneys will be the death of them. The term locked up could also suggest that they will be cleaning chimneys forever. Coffin is also a sense of claustrophobia, being locked up inside a coffin or chimney would be considered suffocating. Stanza 4 makes reference to the bible where by an angel is mentioned which is usually sent from god. This stanza is specifically child like as it has a nursery rhyme quality describing the horror of the nightmare in a child like tone. The angel sets the boys free into a field of laughter and play, things they should be doing, it shows just how horrible life was for the boys by contrasting it with what they should have been doing at their age. Then naked and white referring to the boys, in stanza 5, which means innocence as nakedness is a state of innocence in terms of Christianity. In the dream all their bags left behind bags represent what the boys would take to work but as it was left behind it symbolizes work being abandoned. Again god and angels are mentioned showing reference to the bible, one of the books which was most resourceful to Blake. In the last stanza of the poem it shows the long hours the young chimney sweepers do as it says we rose in the dark early hours of the morning. The very last line is very effective because it shows that the boys have been taught to think that working will bring them no harm this is ironic because the work of a chimney sweeper is harmful to them. The overall message Blake is trying to get across to his reader is the immoral manner in which these children are being treated. The second poem, The Chimney-Sweeper (experience) has many similarities between the first poem. It is not narrated by the young chimney sweeper but an on-looker which shows difference between the two poems. It also is a powerful poem trying to convey the wrong nature of child chimney sweepers. The first line of the poem is a contrast where Blake puts A little black thing with the purity and white of the snow. Similar to the first poem where soot and the white of the boys hair is also mentioned, both make use of anthisesis. This creates powerful colour imagery in the readers mind because it is such a contrasting image. The use of the word thing makes the child seem non human unable to distinguish whether it is a boy or a girl. Black is a reference usually made with corrupt and dirty. Black would imply the clothes that the boy is wearing and the black soot from the chimney that has stained his clothes, it also could mean his personality is corrupt and innocence stripped. A link is again made to the first poem where the child can not pronounce the word sweep so instead says weep giving off distress and sadness of the young child. The child is described as little to induce sympathy from the reader as it shows the childs youth. The part of the narrator is made in line 3 where he is shown as a considerate adult by asking where the childs father is. In line 4 it mentions the parents have gone to church to pray, irony is conveyed here because while the parents have gone to pray the child is suffering, showing distance. Regular church goers didnt see chimney sweeping as wrong as did many during this era, so many put their kids into this job. Stanza two line one has a great shock over the reader as the line Because I was happy confuses the reader because it says he was happy that his parents sent him to an early death. Blake throws this sentence at the reader to show how totally wrong it is to violate the purity of a child. Clothes of death the phrase represents the clothes the child has to wear when they become a chimney sweeper which quickly becomes dirty because of the soot it also suggest the fate of the boy that being death. And smiled among the winters snow the snow that surrounds the boy could represent his innocence but once it was taken away from him he became A little black thing amongst the pure snow. The last line shows how the boys have to conform taught me to sing the notes of woe it echoes poem one as the narrator also had to conform and say the notes of woe It shows the corrupt nature of society the society at this age. In the last stanza rhyme and rhythm is apparent but echoes that of a nursery rhyme again relating to the innocent poem. Rhyming is used sing and king as well as a para-rhyme with the two words injury and misery the para-rhyme stunts the poem and throws it off a constant rhythm, the effect could convey the boy as troubled and unhappy because of his hardship. Reference to religion and the church priest are made, similar to the first poem, monarchy is also mentioned by the word king the relevance these references have reflects Blakes writing as Blake did not like the way the church and monarchy largely ignored the problem, it concerned him. The three things Blake felt had failed him, was disappointed in and strongly against is shown through the last line where it says who make up a heaven of our misery. The blind uncaring nature of the monarchy and church is shown by the line they think they have done me no injury The message conveyed in this poem is apparent at the end of the poem where monarchy and the church are attacked and blamed for the cruelty act of chimney sweeping children. How both have power over many yet do nothing to stop it, Blake effectively shows it by putting it in the perspective of a youth as it evokes more sympathy. The structure of the poem is similar to the first poem all stanzas are written in lines of four and a similar message is conveyed where nothing is being done about the chimney sweeping children and the problem is accepted and ignored. The poem London gives background to the misery of the poor and the gulf between those in power. The title London is a metaphor since it is not solely on the people of London but about society and mankind in general. The man is dazed, wandering the streets and is hearing the cries of the ones suffering chimney sweeps, sighs of the hapless soldier and feels the society should do something about them, the man represents William Blakes views. Mans lack of freedom is apparent in this poem and is the point trying to be made. Blake believed in an equal society and the only way the human spirit could exist and grow happily, he did not believe in human oppression. Control is constantly mentioned throughout the poem. For example in the first stanza chartered is mentioned which means governed by law. It clearly says in the second line that the Thames is chartered which is impossible because you cant control a river. It shows Londons extreme extent of control at that time. Even the mention of chartered streets suggests an uptight lack of freedom setting for Blakes contemporary people. The most powerful metaphor used in this poem is mind-forged manacles found in stanza two the last line. Manacles associated with restriction unable to have absolute freedom, also a common object associated with prison, imprisonment and portraying deep human truth. Mind-forged means the manacles have been created by peoples mind set trapping everyone in restrictions that must be followed. The image created via this metaphor would be a distinct one for Blakes contemporary day because convicts would be seen on the streets making their way to prison or commonly in London, during that era, off to ships for transportation to Australia. The metaphor strongly demonstrates Blakes belief, that the lack of freedom came from the ideas and outlooks placed on them by external authority, mentally people were controlled. The repetition of the word every is a word commonly used in stanza 2 it is to emphasize that everyone is effected by this state of depression and lack of freedom. It is also written in stanza one although relating to the amount of people that have the mark of weakness and woe. Mark is another word repeated found in the first stanza it is to signify the look of distress that is etched on their faces also to mark the lines that have been created because of their worries and weakness. A reference is made that links to The Chimney-Sweeper innocence and experience; this portrays Blakes obvious strong disagreement with the treatment of child chimney sweepers as he mentions them a lot. The next line in stanza 3 says Every blackning church appalls churches at that time were black because of the pollution present and soot coming from the chimneys. On a deeper meaning it could be said that the churches ignorant behavior towards the chimney sweepers problem has blackened them with shame. The irony is that the church is meant to be helpful place where many seek for help but the church chose to ignore and over look the problem. This is what Blake noticed unlike the people living in his society. The second strong image that is painted to the reader is the hapless soldiers sigh They show weakness and woe because they had fought in the French revolution and Runs in blood down palace walls Blake is trying to show that by oppressing freedom of speech, in England, at that time by the government the unhappiness of the English soldier could, its causes were ignored, lead to similar bloodshed here. Images of darkness are made similar to Blakes poems of the Chimney Sweeper (Experience) and (Innocence) through midnight streets The last image that Blake highlights has a shock factor because it talks about child prostitution. This can be seen as a type of child labour similar to Blakes view of the child chimney-sweepers, however instead they are child prostitutes. Also both youths lose their innocence through what society decides to ignore. Youthful harlots emphasises their youth and harlots gives a biblical tone. Blasts the new-born infants tear shows the birth of the child is not a happy event but a curse for the prostitute as it wasnt born out of love but through commerce. The new-born will only mean having to support the child with money, which these young children didnt have, it just continued the cycle of misery. The marriage hearse an oxymoron, what Blake is trying to convey is that the wedding carriage is basically a hearse leading to a kind of death. Men usually didnt marry out of love so would be unfaithful to their wives, they would usually contract a disease from the young harlot, said as the plague in the poem, and then pass it on to their wives and any babies that the married couple may want to have. This contradicts the idea of marriage which is a time that is meant to symbolise joy the contradiction is apparent through the word hearse Blake makes many of his messages clear in this poem, such as the abuse of child prostitutes by cruel adults and the abuse of chimney sweepers. He does this by stating their sad emotion, chimney sweepers cry the hapless soldiers sigh and youthful harlots curse these descriptions have a strong effect on the reader as they simply explain the hardship different people are going through. Blake makes sure he bases it on a wide range of people to convey to his reader that it is affecting everyone not just a small group of society. The Title of the poem The Human Abstract is a poem about the human spirit; abstract suggests non definite intangible quality found in the human brain. He uses a tree to represent the human brain and how it is easily controlled. Blake uses nature to convey his ideas this is shown in the poem A poison tree as well as this poem. His respect for nature is apparent and makes him a romantic writer. The poem has constant rhythm; the rhythm change helps present subject and tone. This poem is hard to understand and the least easy to depict the social message compared to the evil of anger, which Blake explains in A Poison Tree. The structure of Blakes poem consists of 6 stanzas and simple lines to convey his complicated messages. The rhyme scheme is ABAB although odd Para-rhymes are present for example fly and mystery. Many components of this poem echo the bible such as imagery and words. The first stanza has an arrogant tone one which is strange to Blakes writing. The reason for this verse is to show the attitude of several people in the society Blake was living in. A different tone to the rest of the poem is given where the phrases are stated as facts. Blake through the first stanza states that pity, an act of compassion, would not be possible if someone was not poor. Although Blake chose the word make as if society forces people into poverty so they can receive pity. The same is done with the word Mercy if mercy was not present if everyone was happy. Blake could be describing the way life was and trying to put across his message in an ironic way by placing it in the uncaring tone. The stanza is relevant to contemporary times but would shock many in Blakes time because British society was built on the principles of clear inequality, Blake certainly didnt approve of this inequality. An immediate tone change is made after the first stanza where the rest of the poem argues with stanza 1. Through out this poem Blake uses a lot of antithesis, also done in The Chimney-Sweeper, for example selfish love through these controversy phrases and words Blake might be trying to show everyone has an ulterior motive to anything which is usual an act of good nature. He puts mutual fear and peace in the same line trying to convey that there is only peace because would-be enemies are living in fear of each other. Blake makes good use of personification, Cruelty knits a snare, and the use of the word cruelty adds an uneasy quality. Cruelty in this poem is suggesting that all of us have some of this quality in each of us. The suggestion is that Cruelty makes a knitted snare and spreads his bait with care. The image is a strong one because the word choice is odd, knit and care is often associated with care and to place it with cruelty and bait makes it sinister. It then moves onto cruelty sitting with holy fears and watering the ground, to grow the plant, with tears Again images created are vivid and help explain his ideas, things seen as good acts and kindness have been transformed and linked with pitiless words to make it menacing. The tree that is growing is being made up of unappealing qualities Humility takes its roots. To show the tree is not something of beauty and nature soon spreads the dismal shade The colour image created is darkness and creates mystery, often used in Blakes poetry, darkness and mystery foretells the unknown which scares many because it links with fear. Nature is apparent by the mention of a caterpillar and fly which feed on the mystery, they could represent the idea of corruption and sickness. Biblical reference is often pinpointed by Blake, fruit of deceit this reminds us of the Garden of Eden and the fall from grace. This once more makes the reader see the tree as sinister with the inviting fruit that is actually deceitful. Mentioning of the raven conveys bad things as it is seen as a symbol of death. The raven is creating a nest with the thickest shade suggests mystery and shadows of the Human Abstract described. The word Thickest shows its the worst of death and that it is inevita ble. The last line of the poem obviously states the concept of the whole poem that the mysterious tree that has been growing made up of cruelty; humility etc is simply found in the human mind. Blake conveys that its existence is metaphorical rather than literal but the use of a tree shows the stages of growth and how the things surrounding it affect the way it is. The last line is very simple, conflicting with the rest of the poem, and accepting of this idea it shows the accepting nature of the society that Blake was surrounded by. The abstract way in which Blake described the human mind is far from clear given life isnt clear so the poem represents a humans life. The next poem is A Poison Tree a simple poem able to hold and reveal complicated messages. A Poison tree shares the nature aspect with The Human abstract the idea of a tree growing. Although The human abstract tree represents good and evil being part of every ones spirit and mind. In A Poison Tree the growing tree symbolises the growing of hate when anger is not expressed. The title is a central metaphor; its ironic because trees arent perceived as poisonous. The poem A Poison Tree is about anger and if kept inside could grow and become poisonous to one and others. Reference to the bible, like in The Human Abstract, is constantly made and the reader has to have some amount of knowledge on the bible, many in Blakes time understood his references as the bible was the most common book. All through out this poem the rhyming scheme is AABB. Similar to The Human abstract William Blakes mention of nature is common, linking him to the Romantic Movement. Blake conveys, simply, in the first stanza that when angry with your friend you express to them your anger and it will end. He put it simply by using the two words friend and end. Although it is a different situation when angry with your foe, by not expressing his feelings to his foe the anger grew insinuated through the words foe and grow It has a nursery rhyme like quality with simple choice of language and regular rhythmic words. Child-like ton is present I was angry He indicate that his anger and hatred has taken the form of a tree by the term watered By watering the plant with his tears and fears (metaphorically) it will encourage his hatred. The smiles and deceitful wiles represents the sunshine, simple natural metaphor. It could also represent the false attitude towards the foe. The tree then bears an apple, indication of the bible, the story of Adam and Eve where the couple is forbidden to eat the fruit of the tree of knowledge the fruit being an apple. The apple, since it is forbidden is tempting. In this poem the apple is suspicious when it is described as shiny; shiny also makes the apple seem tempting. The foe steels the apple because he knew that it was mine. Darkness is again mentioned in Blakes poem when night had veiled, it is also mentioned in London to represent sinister acts. The narrator is cunning because he uses the apple to capture the enemy knowing that he would eat it because it belonged to him. A sense of immediacy is brought to our attention in the last two lines by the use of enjambment and quick change from past to present. The narrator finds his enemy dead after eating the tempting apple. At this point he is pleased Glad I see My foe outstretched beneath the tree This shocks the reader because the extent he has gone to because he did not express his anger, it then becomes apparent that the narrator is no longer feeling anger but wrath. The way he dies is quick and simple and shows anyone can feel hatred to this extent and perform this cunning deed. Simply Blake conveyed the message that if anger is expressed its good and relieving but if held, it turns into resentment, fear and hatred grows. William Blakes poems do not fit the age in which they were written as his ideas and messages he attempted to put forward have a contemporary outlook. The poems reflect the type of society Blake was living in. In each poem he expresses different controversial ideas; In The Chimney-Sweep Innocence and Experience he puts forward the immoral use of child labourers by putting it in the perspective of a child. In London it is stated how people are controlled easily and how he was against inequality. The message in The Human Abstract however complicated, talks about the human mind and how good and evil are two correlating things. Lastly in A Poison Tree Blake makes it clear that hate, to the extent of wrath, can be present in anyone, and that fear can grow into hate if not expressed. Today Blakes views would not be condemned and most would agree with his ideas. William Blakes views were strongly portrayed in his poems through his poetic devices, language, tone and structure.

Cyclo-oxygenase inhibitors of human diseases

Cyclo-oxygenase inhibitors of human diseases Historical background Cyclooxygenase (COX) inhibitors are a widely prescribed group of antipyretics and analgesics worldwide and are important component in the treatment of inflammatory conditions. Although first COX inhibitor was discovered more than a decade ago their origin dates back to ancient Mediterranean descent1. Back and other body pains where treated using extracts of poplar tree bark and leaves of myrtle. Use of willow bark emerged far more lately and its first appearance was reported in England in 17631. As was later discovered, the essence of the willow bark possessing anti-inflammatory and antipyretic properties was salicin. Further modification of its structural properties allowed generation of salicylic acid that eventually was developed via Kolbe reaction using phenol1,3. In 1899 Bayer company went ahead in synthesising more susceptible derivative of it, acetylsalicylic acid and named it aspirin. Following this phenylbutazone (1949) and indomethacin (1963) came along however the mystery of mechanism of their action in the body was not yet developed. It was not known until 8 years later when an idea surrounding the synthesis of prostaglandins within body was revealed and for which a Nobel Prize in physiology and medicine was awarded (1982)1. It was proposed that first non-steroidal anti-inflammatory drug (NSAID), aspirin, acted upon inhibition of an enzyme that played role in utilising unsaturated fatty acids into biochemical molecules exerting their action in conditions such as inflammation, pain, and fever and platelet synthesis. It was accepted that during changes occurring within stimulated cells and tissues prostaglandins synthesis was taking place 1,3. Structure of COX was isolated in 1976 and its second isoform was confirmed around 14 years later by few different laboratory investigations; investigations which greatly allowed appreciating the nature of first nonselective cox inhibitors NSAIDs in the treatment of human diseases1. 1.1 The pharmacology and chemistry of cyclooxygenase enzyme Cyclooxygenase (COX aka PGG2/H2 synthase) belongs to the family of enzymes known as myeloperoxidases and it is the crucial enzyme in the synthesis of prostaglandins, prostacyclin and tromboxane A2 resullting from the conversion of arachidonic acid (AA) 2,4. This heme-containing COX enzyme is a bifunctional biocatalyst with two interconnected active sites: cyclooxygenase and peroxidase which action involves generation of hydroperoxy endoperoxide PGG2 via cyclooxygenase cycle (Fig.1.) into its reduced form of hydroxy endoperoxide (PGH2) (Fig. 2.) 2,4. Both isoforms of COX enzyme are expressed in endothelial, monocytic and renal cells with COX-2 being more profound in inflammatory and cancer tissues. Both enzymes are characterised by signal peptide, endothelium growth like factor (EGF) region, membrane in-bound domain, catalytic part, interface between monomers and N-linked polysaccharides residues2. The signal peptide in COX-1 consists of 23 residues whereas COX-2 has only 17. The EGF like region constitutes a major part of the interface and is not found in other myeloperoxidases. It is involved in Cys-Cys cross linked bridges with lack of Cys9 in COX-1 and Cys512 in COX-2. The membrane in-bound domain accounts for 33% of overall similarity and 24% of identity within membranous face. This domain is described as consisting of 4 amphipathic a helices that surround the entry to the COX site. The catalytic part is known to be the largest part of the enzyme with remained homology between other myeloperoxidases. 180Â ° rotation between subunits is preserved with chemical interaction between polar, ionic and hydrophobic moieties. Differences in residue positioning prevent heterodimerization and dissociation from facial interaction inactivates the enzymes overall catalytic activity 1,2,3,4,5. Figure 1. Mechanism of COX cycle in cyclooxygenase active site showing free radicals formation denoted by ? prior to PGH2 synthesis in POX pathway (not shown) 2. Attraction of hydrogen atom from Tyr385 by peroxyl radical of PGG2 allows for the regeneration of the steps of the reaction in the COX cycle of prostanoid biosynthesis. The coloured boxes are to indicate the origin of oxygen atoms. PLA2 phospholipase A2, S secretory, C cytoplasmic. Figure 2. A diagram summarising changes made to AA in the distinct active sites of the PGG2/H2 synthase and products formed via action of each catalytic active site 2. 1.2 The nature of cyclooxygenase inhibition in the human body Inhibition of cyclooxygenase action is desired in the treatment of human diseases. Not only because it suppresses the inflammatory production of prostaglandins in the conditions such as: dysmenorrhoea, rheumatoid arthritis, osteoarthritis but also because it prevents platelet aggregation, suppresses tumour growth and prevents cancer5. Until 1994 it was not clear by which mode, mechanism or process inhibition of COX was carried out. Just complexation studies between COX and flurbiprofen allowed insight into molecular basis of COX inhibition. The investigation led by Garavito and his colleagues proposed such model of inhibition. In his model it was suggested that the enzyme in question possesses long hydrophobic path that originates from in-membrane bound moiety up to the heart of the dimer subunit. Blocking this channel stops the endogenous substrate (AA) from binding hence possible intervention in the process of prostaglandins biosynthesis5. 1.3 The types of cyclooxygenase inhibitors in the treatment of human diseases There are several types of COX inhibitors available in the treatment of human diseases. The very first one, aspirin, is known to act through non-selective and irreversible manner. As this manner suggests aspirin binds to both types of COX enzyme by acetylating Ser530 residue upon covalent modification. Consequently effects such as risk of excessive bleeding, ulcer formation or foetal deformation limit the use of aspirin in dealing with long term diseases. Nowadays it is mainly considered as the important component in the treatment of cardiovascular conditions due to its anti-platelet activity 1,3. Other types of non-selective NSAIDs such as piroxicam, ibuprofen or diclofenac, constitute majority of therapeutic agents being prescribed however due to harmful effects they are being considered less effective in the long term treatment. The damage to the gastrointestinal (GI) system is due to inhibition of COX-1 expressed in GI mucosa which results in formation of ulcers with associated bleeding. Therefore since the main target for choosing those drugs is found to be of inflammatory nature (inhibition of COX-2) they are nowadays preferred in topical dosage forms 1,3,5. The consequence of the undesired effects caused by non-selective COX inhibitors targeted new approach towards development of more specifically acting agents. The era began on discovery of the second isoform of cyclooxygenase and introduction of first COX-2 selective agent (1999) was introduced to the market within 10 years since its discovery with celecoxib and rofecoxib for the treatment of arthritis. The discovery proposed mechanism of actions of both enzymes within the body with COX-1 possessing more constitutive effects especially in GI tract. It was therefore suggested that COX-2 was an inducible form in conditions such as inflammation and pain, symptoms desired in treatment of human diseases associated with the effects of COX-2 isozyme 1,3. 2. ASPIRIN THE ORIGINAL COX INHIBITOR (Joyce) 2.1. Pharmacology and chemistry of Aspirin Plant ingredient salicin was discovered in the willow bark and leaves in the 17th century by a greek physician (Hippocrates) who prescribed it as an analgesic and antipyretic. Further into the 17th century a crude form of salicylic acid was made by a German scientist (Charles Frederic von Gerhardt). This was followed by production of a purer form of salicylic acid by another German chemist (Karl Johann Kraut). Finally in 1897 a German chemist Felix Hoffmann, who worked for the pharmaceutical company Bayer, was assigned the task to find a better derivative of salicylic acid. He also had his own personal reasons for wanting to find a better derivative. His father had been taking salicylic acid for his arthritis pain but could no longer take it without vomiting3,7. In 1889 Hoff man then found a way of acetylating the hydroxyl group on the benzene ring of salicylic acid to form acetylsalicylic acid. Hoffman father tried the new derivative and it was pronounced effective. The name ‘ASPIRIN was given to the drug by Bayer chief pharmacologist Henrich Dreser7. Aspirin was found to have antipyretic, analgesic and anti-inflammatory effects. It does this by inhibiting cyclo-oxygenase(COX) or prostaglandin endoperoxide synthase(PGHS) enzyme irreversibly. COX is responsible for cyclizing arachidonic acid and adds the 15-hydroperoxy group to form PGG2 which is the precursor to prostaglandins. An enzyme perioxidase is responsible for reducing the hydroperoxy group of PGG2 to the hydroxyl group of PGH2.(4)(See Figure 15- prostaglandins synthesis) Prostaglandins can be described as chemical mediators that produce a variety of strong physiological effects in the body. Most importantly they are responsible for the activation of the inflammatory response, production of pain, and fever. There are three isoforms of the COX enzyme of which aspirin has an effect on two which are COX-1 and COX-2. Aspirin binds covalently modifiying COX-1 through acetylation of its Ser-530 and COX-2 through acetylation of its serine 516 residue by placing a bulky constituent (acetyl) and this directly inhibits binding of arachidonic acid. Aspirins action is more potent against COX-1 than against COX-2. This difference in inhibition of the two COX enzymes by aspirin is due to the larger volume of the COX-2 active site produced by the Val-523 substitution at the side pocket. (1,7, 9) The difference in the size of the active site has been exploited by pharmaceutical companies to develop selective COX-2 inhibitors (section 4) COX-1 is an essential enzyme expressed in majority of tissues and also in platelets. It is responsible for prostaglandin production involved in homeostatic mechanisms e.g. platelet aggregation, gastric wall protection, regulation of renal blood flow and initiation of labour in childbirth. In contrast, COX-2, is an inducible form which becomes up regulated by inflammatory mediators such as cytokine (Interleukin and tumour necrosis factor). 2.2 The problems associated with aspirin(1, 10) a. Unwanted effects GASTRIC PROBLEMS The inhibition of COX 1 can produce gastric disturbances as an unwanted effect because the prostaglandin production in the GI tract is a homeostatic mechanism to protect the gastric mucosa. It causes inherent symptoms like heartburn; dyspepsia, nausea, and abdominal pain. (1, 10)This effect can cause Aspirin users to change or discontinue its use. Some of these inherent symptoms are quite common for most NSAIDs. Secondly it can also causes gastro duodenal mucosal lesions such as erosions and asymptomatic ulcers, which may or may not heal spontaneously; and finally more serious gastro ulcers with life-threatening complications like perforation, symptomatic ulcers, and bleeding ulcers. Symptoms of this could be black, bloody, or tar like stools or vomiting/coughing up blood REYES SYNDROME Reyes syndrome is a collection of symptoms consisting of altered consciousness, convulsions, low blood glucose, and enlargement of the liver associated with fatty infiltration of the liver. It is a deadly disease, which can strike any child, teenager, or adult without warning. All body organs are normally affected, but the liver and brain are antagonised the most. In 1965 it was stipulated that Reyess syndrome can be caused by the administration of aspirin in children under 16years of age. There is no discovered mechanism for the role of salicylate in this but it is thought that aspirin enhances the release of tumour necrosis factor which induces apoptosis of cells which can cause inflammation, viral replication e.t.c. SALICYLISM This is caused by the excessive ingestion of aspirin. There are two main pathways in the metabolism of aspirin. (10)Phase 1 reaction that involves the oxidation of aspirin to salicylic acid by a cytochrome P450 monooxygenase. By addition of a reactive group (OH) to get it ready for conjugation to a soluble component and hence aid excretion. This conjugation involves the attachment of small polar molecules glycine and gluconoride to salicylic acid. This results in further deactivation of the aspirin and the production of water-soluble metabolites that will be readily excreted in the urine or bile. The pathway conjugated with glycine, is the one that is easily overloaded in cases of toxicity. Thus elimination of salicylic acid slows down and accumulation leads to a variety of side effects. Below are the pathways showing oxidation and conjugation. This excess salicylate produces toxic effects include below. Ringing in ears Hyperventilation which causes increase in CO2- respiratory alkalosis, Dehydration: increased water loss due to hyperventilation Loss of carbonic acid metabolic acidosis. This in turn will reduce the blood pH, and make aspirin return to its non-ionised form allowing free aspirin in the blood stream. Hyperthermia. These pathways overload uncouples the energy producing processes (oxidative phosphorylation) of the mitochondria thus causing production of heat rather than ATP. Fatality especially in children Interactions with other drugs Reduced effect of aspirin if given with ibuprofen and avoid concomitant use of aspirin with NSAIDS due to increased side effects. Increase risk of bleeding when aspirin is given with coumarins, SSRIs, clopidogrel, illoprost, and sibutramine, Aspirin enhances effect of Heparins, Phenytoin, Valporate, Aspirin antagonises effect of Spirolactone, Sulfinpyrazone and Probenacid Rate of excretion of aspirin is increases by some antacids. The effect of aspirin on the gastrointestinal tract may be enhanced by the intake of alcohol and corticosteroids. 3. NON STEROIDAL ANTINFLAMMATORY DRUGS NON SELECTIVE COX INHIBITORS (Christina) 3.1 Isozymes of Cyclooxygenase Cyclooxygenase has various isozymes. The main isozymes are COX-1 and COX-2, however there is now evidence of a third form- COX-3. COX, originally known as prostaglandin H synthase is responsible for the oxidation of arachadonic acid to prostaglandin G2 and prostaglandin H2. It catalyses the reaction in which the arachadonic acid substrate and two molecules of O2 are converted to prostaglandin G2 and then in the perioxidase reaction Prostaglandin G2 is reduced to PGH2 by a 2 electron reduction. The COX isozymes are heme containing enzymes that are homodimers. Each monomer contains three main domains; A membrane binding domain, a N-terminal epidermal growth factor domain and a C-terminal catalytic domain. COX-1 is made up of 602 amino acids while COX-2 is comprised of 604.3 The catalytic reaction in COX takes place in a hydrophobic channel in the core of the enzyme while the peroxidise reaction takes place in the heme containing region near the surface of the enzyme. The membrane binding domain consists of four alpha helices with one helix that fuses with the catalytic domain. These helices congregate around an opening and through these openings fatty acids and NSAIDS are considered to enter the active site. The COX-1 isozyme is considered a constitutive enzyme. It is present in high volumes in most cells and tissues i.e. renal collecting tubules, monocytes, endothelium etc. However COX-2 is hardly noticeable in most cells, it is an inducible enzyme so it becomes more abundant in cells or tissues when macrophages are activated or by any other inflammation mediators e.g. TNF-a (tumor necrosis factor-alpha) or IL-1 (interleukin-1).5 Both COX-1 and COX-2 isozymes are attatched to the endoplasmic reticulum and nuclear envelope. The COX isozymes need to be N-linked glycosylated to enable them to be folded and attatched to the endoplasmic reticulum and nuclear envelope. The COX isozymes have very similar structures for their binding site, catalytic mechanisms and produce the same biosynthetic products3 COX-3 COX-3 a third isozyme was discovered in 2002 by Simmons and co-workers. They conducted a study on dogs and this resulted in them discovering a novel COX-1 splice variant termed COX-3 that was sensitive to acetaminophen (paracetamol). It was suspected for a while that acetaminophen worked by inhibiting a different specific isozyme due to the fact that it did not directly inhibit COX-1 and COX-2 very effectively at therapeutic concentrations but it generated prostanoids in neuronal systems. 3, 15 The Simmons and co-worker group showed that acetaminophen was the actual target for COX-3, and that it acted separately from COX-1 and COX-2. 3 Canine COX-3 is a membrane bound protein consisting of 613 amino acids with a molecular weight of ~65 kDa. It has a high expression in cells and tissues like COX-1 suggesting it may be a constitutive enzyme. However the question that needs to be asked is if generalisations can truly be made on the presence of COX-3 in humans based on Canine studies, so future experiments need to be designed to clarify whether a human COX-3 actually does exist that acts independently from COX-1 and COX-2 in vivo. 14 NSAIDs are known to inhibit COX in order for them to exhibit their anti-inflammatory actions, a structural NSAID binding study was carried out. The COX-1 active site contains a long hydrophobic channel that extends from the membrane binding domain to the core of the COX monomer. The tip of the COX active site houses Tyr385 that is located near the heme iron. Ser530 is positioned just below Tyr385 and that is the site for aspirin acetylation. Glu524 and Arg120 are positioned at the mouth of the COX-1 channel. A typical NSAID such as fluobriprofen, when introduced to the COX enzyme, its carboxylate moiety is usually directed towards the mouth of the COX-1 channel in order for it to be positioned in the most ideal place that will allow it to interact with the two polar residues Glu524 and Arg120. From these studies a better insight into the binding profiles of NSAIDs were observed. Non selective NSAIDs can bind in three different ways: Reversibly (e.g. Ibuprofen) Fast, low affinity reversible binding followed by a higher affinity, time dependant slowly reversible binding (e.g. fluobriprofen) Rapid, reversible binding followed by a covalent modification of the enzyme (e.g. Aspirin) 3 Arg120, Glu524, Tyr355 and His90 form a network of hydrogen bonds at the entrance of the COX channel acting like a gate to the binding site. NSAIDs generally bind between the upper portion of the COX channel near Tyr 385 and Arg 120 which is at the mouth of the COX channel. 3 Through the use of hydrogen bonding and electrostatic interactions, the carboxyl moiety of acidic NSAIDs like fluoribiprofen interact with Arg120 in both COX isozymes. The significant differences in the structure of the binding sites for both COX isozymes has been manipulated to enable the design of selective COX-2 inhibitors. In the COX-2 active site there is an extra accessible pocket due to the presence of a smaller valine amino acid residue at position 523 and a valine substitution at position 434, unlike COX-1, this difference increases the overall volume at the COX-2 active site by about 20%. 1 This means that due to reduced steric and ionic crowding at the mouth of the channel by Arg120, non acidic selective COX-2 inhibitors can show an enhanced and specific binding to the COX-2 enzyme. Another structural difference exists at the amino acid residue 513 where COX-1 has a histidine residue and COX-2 has an arginine moiety. 1 These small differences provides flexibility in the substrates that can be utilised in the COX-2 active site. 3.2 Problems Associated With Non Selective Non Steroidal Anti-Inflammatory Drugs NSAIDs are one group of drugs that are regularly used by the worlds population to relieve pain, reduce inflammation and lower temperature. They are COX inhibitors and act to inhibit the catalysation of arachadonic acid to PGH2. COX-1 is constitutively present in most cells while COX-2 is induced by chemical mediators of inflammation and activated macrophages.13 COX-1 and COX-2 as mentioned above have 2 specific roles. The 1st role gives PGG2 and the other role is in the peroxidise reaction that gives PGH2. Both COX-1 and COX-2 inhibitors work by inhibiting the 1st and main role i.e. inhibiting the conversion of arachadonic acid to PGG2. COX-1 and COX-2 possesses hydrophobic channels within their core. The classical NSAIDs exhibit their effects by blocking these enzymes halfway down the COX channel near Tyr385 and the Arg120 which is at the mouth of the COX channel by hydrogen bonding to the Arg120 residue. This results in the prohibition of any fatty acid substrates from entering the catalytic domain of the COX enzyme.3 In COX-1, these drugs tend to inhibit the enzyme quickly yet generally the inhibition is often reversible, however in COX-2 the inhibition is time dependant and often results in irreversible inhibition. As mentioned before, the COX-1 and COX-2 isozyme differ slightly. In the COX-2 active site there is an extra accessible side pocket due to the presence of a smaller valine amino acid residue at position 523 instead of isoleucin as in COX-1. This is important for understanding why some NSAIDs are selective for the COX-2 isozyme.13 There are a number of side effects associated with traditional NSAID therapy. NSAIDs can cause renal failure, liver damage/disorders, aseptic meningitis, skin reactions and bone marrow disturbances which can interfere with bone fracture healing. However amongst them all gastrointestinal (GI) toxicities is amongst the most common. These are believed to arise from the inhibition of COX-1 in the gastric mucosa.14 GI toxicities In humans and other species it has been shown that COX-1 not COX-2 is constitutively expressed throughout the GI tract.13 COX-1 is responsible for the synthesis of prostaglandins like PGE2 and PGI2 which are responsible for protecting the GI mucosa by reducing acid secretion in the stomach by the parietal cells, increasing blood flow in the mucosa and stimulating the release of viscous mucous. This leads to conditions of ulcers, dyspepsia, diarrhoea, nausea and vomiting and can even lead to gastric bleeding in some cases. These undesirable side effects have led to the development of COX-2 selective inhibitors. These drugs are effective anti-inflammatorys and reflect good analgesic effects. They have considerable less gastric damage due to the fact they selectively inhibit COX-2 with minimal action on COX-1. Unfortunately the use of COX-2 selective drugs has been associated with increased incidence of myocardial infarction and stroke.3 Renal effects Prostaglandins especially PGE2 and PGI2 are involved in regulating renal blood flow and vascular tone. Recent studies have shown that COX-2 is constitutively expressed in the macula densa, epithelia cells lining the ascending loop of henle and medullary interstitial cells of the renal papillae, while COX-1 is constitutively expressed in the collecting ducts, loop of henle and in the vasculature. The COX-2 enzyme is associated with normal renal function and inhibition of COX-2 results in NSAID-induced sodium retention while inhibition of COX-1 results in a disease in glomerular filtration rate.3 This conclusively tells us that both COX-1 and COX-2 are involved in the physiology of the kidneys. However therapeutic doses in patients with normal renal function are at little risk of renal complications. It is mostly neonates and the elderly who are more susceptible as well as patients with heart, liver or kidney disease. 4. SELECTIVE COX 2 INHIBITORS (Nadine) 4.1 Reasoning behind selective inhibition 4.2 Benefits and risks 5. MECHANISM OF ACTION OF COX INHIBITORS IN HUMAN DISEASES 5.1 Analgesic (Joyce) Pain can be defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is a self protection mechanism which helps of forces us to identify danger and move away from it. It is one of the main symptoms used to identify a condition in medicine. Removing pain is very essential in terms of either eliminating the disease or condition or in fact suppressing its effect. This can be done by the use of medicines called analgesics. Pain receptors also called nociceptors are present on special nerve fibres that are sensitive to noxious of harmless stimuli. The stimulation of these receptors are on A-delta and C-fibers which are located in skin, connective tissue, viscera, muscle e.t.c. COX inhibitors act by blocking transmission to peripheral nerves. Pain associated with I. Arthritis Arthritis is the inflammation of joints. The inflammation and movement of the joints cause extreme pain in the sufferer. There are two major types a. Osteoarthritis(10) This is a chronic disease that features the breakdown of the joints cartilage. Cartilage is flexible connective tissue found in between joints that cushions or protects the ends of the bones and allows easy mobility of joints. This breakdown of cartilage causes the bones to rub against each other creating friction, causing joint tension, pain and loss of mobility in the joint. There are different types of arthritis of which osteoarthritis is most common; it can also be referred to a degenerative joint disease. There are two types of osteoarthritis, primary of which is associated with old age, general wear and tear of the cartilage. And secondary where it occurs where there is a cause example obesity, trauma, or hereditary. Treatment: Paracetamol may be considered as first line therapy for Osteoarthritis patients with mild to moderate pain. If the pain does not respond to paracetamol or patient has severe symptoms then other traditional NSAIDs like Ibuprofen, diclofenac or coxibs should be used. Coxibs have shown to produce reduced GI side effects. However they have the probability of increasing cardiovascular risk because they inhibit prostacyclin production in endothelial cells but not thromboxane in platelets, hence this can increase the chance of a thrombus formation. The choice of a coxib or a specific NSAID should be based on the patient characteristics and risk factors. b. Rheumatoid arthritis(12 ) This is an autoimmune disease of unknown origin whose major characteristic is the inflammation and erosion of the synovial membrane or synovium. This membrane lines and surrounds the joint and synovial cavity. The synovium secretes a slightly viscous, clear fluid known as synovial fluid, which lubricates cavity that lies between the cartilage and joint on the bone. In Rheumatoid arthritis accumulation of the synovial fluid builds up within the joint space and causes inflammation. This makes the joint look and feel swollen. Rubor occurs do to the increased blood flow to the area because of inflammation. In conditions of long-term RA, joint degeneration can occur causing mobility to be very painful and restricted. Treatment: Aspirin used to be used to treat RA but because of its GI toxicity. The use of aspirin as first line of therapy has been superceded by other NSAIDs. There are a large number of NSAIDs that have been invented since aspirin, but have similarities in toxicities e.g. Ibuprofen, naproxen meloxicam, etodolac selective COX-2 inhibitors have been invented to control inflammation. These drugs were designed to combat the gastrointestinal risk of NSAIDS, but there are concerns of increases in cardiovascular risk. II. Cancer (11) Can be defined as an abnormal growth of cells as when a group ofcellsdisplayuncontrolled division,invasion, and sometimesmetastasis. Cells become cancer cells because of its damaging effect to the DNA of the cell. A normal cell will try to repair damaged DNA but in a cancer cell it replicates with the damaged DNA. The cancer cell continues making new cells that the body does not require. The most common cause of cancer pain is infiltration of the tumour into bone. Bone metastases occur as a consequence of different types of cancer. Another mechanism of pain apart from bone metastasis is the secretion of Prostaglandins by carcinomas. For this reason, NSAIDs should be included in any regimen to control pain associated with bone metastasis. Because NSAIDs do not activate opioid receptors, they can provide additional pain relief when combined with an opioid analgesic. Thus, combining an NSAID with an opioid analgesic may provide adequate pain control with a clinically significant reduction in opioid dose. This opioid-sparing effect of NSAID therapy allows the clinician to diminish the side effects associated with opioid therapy without sacrificing pain control. Coxibs: Another Option for Cancer Pain Management(11) The recent introduction of the coxibs, on their use in cancer patients is still being studied. Oncologists are replacing NSAIDs, with the use of coxib, because of the improved safety profile compared to traditional agents. Surgical oncologists are exploring the use of coxibs both preoperatively and during the post-operative period to reduce opioid usage in order to speed the recovery process 5.2 Anti-pyretic (Nadine) 5.3 Anti-inflammatory (Christina) To date there are over 100 inflammatory diseases- each of which causes the degeneration of connective tissue in one or more parts of the body. These include: Rheumatoid Arthritis Osteoarthritis Atherosclerosis Irritable Bowel Disease Alzheimers and many more. Inflammation is characterised by dolor, rubor, calor and tubor, its one of the bodys ways of responding to harmful stimuli, pathogens, injury or disease. These usually initiate an acute or chronic inflammatory response. Arthritis is a general term used to characterise inflammation in the joints. Rheumatoid arthritis describes arthritis that occurs on both sides of the body i.e symmetrical. These usually occur in the wrists, hands and knees. It is not known what causes this disease many theories have been put forward but it happens when the immune system begins to attack the joints. A number of anti-inflammatory drugs are available worldwide and are widely used to relieve pain, swelling and inflammation associated with soft tissue inflammation. A number of these drugs act via the inhibition of COX. When you experience pain and inflammation from arthritis, an increase in microvascular permeability occurs selectively in post-capillary venules. The endothelial cells undergo conformational change leading to vascular leakage through gaps between the adjacent endothelial cells. At the site of injury phagocytes are attracted and move into the affected tissue along with plasma. The plasma causes the associated swelling observed in inflammation and the phagocytes engulf dead cells and bacteria. Prostanoic acids are