My Favorite Leader †Zhou Enlai Essay

Abstract As is known to us all, Zhou Enlai, as a communist party member, the first premier and foreign minister of the People’s Republic of China (PRC), has a high reputation from home and abroad. This paper includes four parts in total. It starts with the brief introduction to Zhou Enlai and then pays more attention to the second part about his contributions. Following is the third part about evaluations from domestic and international. The last part comes to the conclusion. Key words: Zhou Enlai reputation contributions evaluations I. Introduction Zhou Enlai was born in Huai’an, Jiangsu Province on 5 March 1898, and died in Beijing on January 8, 1976. Zhou, an important member of the Chinese Communist Party (CCP) from its beginnings in 1921, was the first Premier of PRC, serving from October 1949 to January 1976. Though Zhou severed as the Chinese Foreign Minister just from 1949 to 1958, he was a master in policy implementation, with infinite capacity for details. His skills and ability of diplomat impressed people all round the globe. He was of great help in consolidating the control of the Communist Party’s rise to power, forming foreign policies, and developing the Chinese economy. II. Contributions To the liberation of the Chinese people and the foundation of a new China As I have mentioned in the first part, Zhou was born at the end of the 19th century, when China was suffering from internal and external. So, Zhou has dedicated himself to the cause of the liberation of the Chinese people since he was young. Between 1920 and 1924, he studied in France and Germany under a work-study program and spread Marxism among Chinese students and workers living there. He joined the Communist Party of China in 1922. During the period of the Great Revolution, he took an active part in the Northern Expedition and made important contributions to the overthrow of the reactionary rule of the northern warlords. He was also one of the leaders of Nanchang Uprising and one of the founders of the People’s Army after the failure of the Great Revolution in 1927. In 1935, Zhou played an important  role in supporting Mao Zedong’s propositions at Zunyi Conference which helped make the Long March of the Red Army a great success. When the Red Army arrived in Northern Shaanxi Province, Zhou, working under the Central Committee of the Communist Party of China (CPC), on behalf of the Communist Party, held talks with Chiang Kai-shek who adopted measures to firstly maintain internal security and then repel foreign invasion, facing the Japanese invasion to Shenyang, China. During the negotiations, Zhou firmly carried out Chairman Mao’s policy, skillfully compelled Chiang Kai-shek to stop the civil war and successfully led to the peaceful settlement of the Xi’an Incident, and thus promoted the formation of anti-Japanese national united front. In the Liberation War of China, he spared no pains to assist Mao Zedong in organizing and commanding the Three Great Campaigns and establishing the new China. To Diplomatic Relations After New China was founded, Premier Zhou also worked as the Foreign Minister for nine years, during which he made painstaking efforts to develop the basic diplomatic policies and form the Foreign Ministry, including formulating rules, systems and diplomatic disciplines. The Five Principles of Peaceful Coexistence proposed by Premier Zhou that † mutual respect for territorial integrity and sovereignty, mutual non-aggression, non-interference in each other’s internal affairs, equality and mutual benefit, and peaceful coexistence † remains the most important norm and standard which officials of the Foreign Ministry must abide by nowadays. The Geneva Conference In April 1954, Zhou, together with the delegation of the People’s Republic of China, attended the Geneva Conference, which was to settle the ongoing Franco-Vietnamese War. His patience and shrewdness assisted the major powers involved (the Soviets, French, Americans, and North Vietnamese) to reach the agreement ending the conflict, and made it possible that the independence of the three countries—South Vietnam, Laos, and Cambodia got the international recognition. Meanwhile, on behalf of the Chinese Government, Zhou put forward the five principles of peaceful coexistence as the criterion for the relationship between countries. The Asian–African Conference In 1955, Zhou was a prominent participator in the Asian–African Conference held in Indonesia. At the conference, Zhou skillfully maintained the right to possess Taiwan, demanded the approval of the People’s Republic of China, put forward his stand for â€Å"peaceful coexistence† and against â€Å"colonialism†, advocated â€Å"seeking common ground while putting aside differences† and made it possible that, the conference produced a strong declaration in favor of peace and actively carried out the peaceful coexistence of China’s foreign policy. The Sino-American relations By the early 1970s, Sino-American relations had begun to improve. In January 1970, the Chinese invited the American ping-pong team to China, initiating an era of â€Å"ping-pong diplomacy†. In 1971, Zhou met secretly with President Nixon’s security advisor, Henry Kissinger, who had flown to China to prepare for a meeting between Richard Nixon and Mao Zedong. After these meetings, Zhou successfully let the United States agree to allow the transfer of American money to China, to allow trades between American-owned ships and China (under foreign flags), and to allow Chinese exports into the United States since the Korean War. What’s more, the United States publicly acknowledged that Taiwan was an inalienable part of the People’s Republic of China. To promote the people’s well-being During the establishment of the new Chinese government, he succeeded in getting support from people from all walks of life, which provided a solid foundation for the construction of the Chinese society and the consolidation of the new China. First foreign minister as he was, Zhou made it possible to create an international environment favorable to China’s construction and to promote world peace and human development. In 1954, he proposed the four modernization goal of constructing a modern industry, agriculture, transportation industry and national defense, which promoted the rapid development of the national science and technology. During the Cultural Revolution, he exerted himself to keep order in the critical situation, and made a great effort to save comrades being persecuted or imprisoned. In 1975, on behalf of the Party, he reintroduced his â€Å"Four Modernization†Ã‚  giving people the confidence and courage to reconstruct China having been destroyed and confused by the Cultural Revolution, III. Evaluations From domestic After his death, one million five hundred thousand people came to see his coffin, and memorials for him were held everywhere. One of the memorial reports devoted to Zhou Enlai wrote: â€Å"He looks to have left nothing for us. But†¦he have hundreds millions of children and grandchildren, and all the land of China is grave for him†. Qian Xuesen, father of the two bombs, once said, â€Å"According to what many non-party people said, they had no idea of the communist party of China until they got to know Zhou Enlai and it was because of him that they began to believe in the CCP.† The writer Bing Xin expressed her admiration that â€Å"Premier Zhou Enlai is the first perfect in the hearts of billion people of 20th century†. From international On January 8, 1976, it was the exact day of Zhou’s death, in front of United Nations Headquarters in New York, the United Nations flag down a half-mast. The UN Secretary, who named General Kurt Waldheim, said, â€Å"In order to mourn Zhou Enlai, the United Nations is to half-mast. There are two reasons for me to make this decision: Firstly, China is an ancient civilization with many countless treasures of gold and silver, but she has no penny of Premier Zhou’s deposits; Secondly, China has a population of one billion and accounts for 1/4 of world’s population, but she has no child of Premier Zhou.† The First Lady Jacqueline Kennedy once said: â€Å"In the world I only worship one man, that is, Zhou Enlai.† Sihanouk lady Monika also said: â€Å"Zhou Enlai is my only idol!† To conclude this part, these evaluations not only mirror his incomparable wit diplomatic skills, but also reflect our beloved Premier Zhou noble characteristics admired in t he world. IV. Conclusion As I have mentioned above, Zhou Enlai enjoys a high reputation in China as well as in other countries, because of his incomparable diplomatic skills and devotion to the cause. Zhou devoted himself to his cause, making unremitting efforts to spread Marxism, making contributions to the  liberation of the Chinese people and the development of China and sparing no pains to promote the Chinese people’s well-being and the peace of the world. Bibliography 1. http://zh.wikipedia.org/wiki/å‘ ¨Ã¦  ©Ã¦  ¥ 2. http://baike.baidu.com/view/1751. 3. http://www.baike.com/wiki/å‘ ¨Ã¦  ©Ã¦  ¥ 4. Gao Wenqian. Zhou Enlai: The Last Perfect Revolutionary. NY: Public Affairs, 2007. 5. Lee, Chae-jin. Zhou Enlai: The Early Years. Stanford, CA: Stanford University Press, 1994. 6. Levine, Marilyn. The Found Generation: Chinese Communists in Europe during the Twenties. Seattle, WA: University of Washington Press, 1993. 7. Wilson, Dick. Zhou Enlai: A Biography. New York: Viking, 1984 8. Tang Jiaxuan. Tang Jiaxuan Elaborates Zhou Enlai’s Diplomatic Thinking in Tianjin Nankai Middle School. ä ¸ ­Ã¥ Å½Ã¤ º ºÃ¦ °â€˜Ã¥â€¦ ±Ã¥â€™Å'å› ½Ã¥ ¤â€"ä º ¤Ã©Æ' ¨

The Wounded Platoon

Being currently in the military I have mixed reactions when viewing this video. I perform the same role as â€Å"Doc† Krebs did, but for the Air Force Reserve. There Is a lot to consider when discussing this documentary. It was well constructed In the sense that those interviewed held various positions representing nearly every step of the larger process that is the war. First I would like to discuss the issue of battle itself. Few of our nation's military actually sees combat, it is largely support for those who do. Of those who are placed In a combat situation the number of those is sustained combat day after day Is even fewer.Infantry during an offensive tactical plan are typically those who have suffered the worst. To make matters worse this particular war is extremely taxing of a person's psyche. Unlike most wars of the past the enemy is not readily identifiable. They wear no uniforms they blend in with the population. Threatening the locals into keeping quiet about which buildings they are in is not uncommon. It is no wonder that returning soldiers are scanning rooftops or firing at the first male they see viewing the site of an explosion. Who Is to say they didn't set It off?Often the explosion from an DIED Is the first wave of an oncoming attack and the gunfire is not far behind. It is easy to say that they should know better sitting on your couch watching this video. But nine months into a deployment especially one where you are on the offensive, not all people are strong enough to know the difference in that split second. The truth is we will never know. Many of the soldiers Interviewed trace the root of their problems back to the death of SST Huh. This was the first of many multiple traumas they encountered. They ere not yet numb to the effects of war.Numbness In itself Is a survival mechanism; as mentioned by a troop in the video, that is necessary to perform at the level needed. In that instant it's kill or be killed, nothing else matters. I t also was especially tragic since the SST that was killed was so well respected and liked. Some of the members did seek help and this is where we get our first glimpse of the larger problem. The speech given by George Bush sending an additional ASK troops Into battle sets off a chain reaction. There are only 25% of young people In this nation that are insider â€Å"fit† to join the military.This is due to a number of reasons such as weight, fitness level, health status, previous surgeries and intelligence level to name a few. It also takes a considerable amount of time from the start of a recruit signing the papers to get them to basic training, which can take months in itself. Then they must be able to complete that successfully and move on and successfully complete their lob specific training. There Is additional training specific to the region and special tactics that also must be completed before a member is even eligible to deploy.That is even if they are infantry as pr eviously mentioned, most of the military does not perform that role. So this brings us to the decisions made by the top level command. Does the military typically allow criminals? No. Do they allow those with pending charges to deploy? No. Do they allow those who are mentally unstable to deploy without first getting treatment? No. Until this war they didn't allow All of these factors security threat overseas, and it worked. A multitude of factors that will forever remain unknown to everyone except the few who made the rules and we will fully know what he rational was.With that being said when the president says you must send this many men, you do. In an ideal world there would be enough to go around. Sure they could have pulled from another base. But what the video doesn't address is anyone else's deployment cycle. This platoon was Just one of many in the same situation. Do you send someone over to Iraq for another year 2 months after they have been reunited with their family? The g eneral population and the vast majority of the military itself do not know the manning of the force or who is actually eligible to deploy out of those who are in. It is certainly a tough call to make.I'm certain that those who made it knew that there would be a downfall in some regard. In this case it is the medical system. The onset of this year we Just completed, has saw a tremendous surge in life- changing injuries and service connected disabilities. As mentioned in the video it is an abnormal situation to be placed in. Many of those who were shown in the video were deemed unfit for continued military service following their deployment, specifically for PETS. A diagnosis of PETS cannot be made initially after a traumatic vent, the symptoms must be present for several months and disrupt daily functioning.Irritability, a sense of being on guard, short temper, easily startled and nightmares are some of a plethora of symptoms experienced. Access to care is another shortfall mentioned in this video. Some of the soldiers did not seek treatment due to stigma. Others such as Nash sought treatment too late after he had resorted to drugs and alcohol first. I will say that the military did fail them in the sense of the initial treatment. I wish I knew why this was the case. I can only speculate that it is due to not being fully aware of the tuition, money and a lack of available resources to treat these members.This brings us to another failure not mentioned in the video. It is unclear what role the soldiers next in their chain of command (direct supervisor) played in this process. They could have advocated for the member, but more importantly they could have simply been there and stuck with them through every aspect of their treatment giving them support at every turn. It is impossible to tell from the video if an attempt was made and the supervisor was shut out, or if one of these men portrayed was the supervisor of the others. That is how the leadership system brok e down.There is absolutely no way that the commander is responsible directly. Commanders are only informed of a patient seeking mental health treatment and they follow the recommendations given by those who actually evaluated the patient. They are given zero information on the diagnosis. Secondly they would be completely unaware of their subordinates behavior off duty. The failure of the mental health system in the military is not surprising. The VA system is shambles and has been before the influx of patients since the onset of this ar.Staffing and overcrowding is commonplace, at least it would appear the federal government cannot turn a blind eye anymore and is addressing this issue. The mental health system has strict rules about duty limitations and determines who is eligible for continued service based on condition but it is obvious in this case they if this process was started on these members as it can take months for a member to be considered at maximal medical improvement. It is only at this point after the government has done everything in their power to aid the member that they can aka the decision to retain or discharge the individual.They simply may not have had the time, or the member may have forced leadership's hand by committing other faults such as felonies as evidenced in the video. It is certainly disheartening to see our military portrayed in this fashion although for some it is a reality. Despite what is shown in this video I feel that our mental health in the US military is performing better than ever before and operates at a high level. Certainly they could use more resources and staff but that cost money that may not be slotted for this particular concern.Budget drives every action in Washington and sometimes it takes a crisis before those who serve us will listen. It will take years to rectify the VA system, and there will also be problems and people lost in the system as they try to seek help as they are exiting the military by choic e or otherwise. I am proud to serve in the military and help those who are wounded, physically or psychologically and will continue to do so. You must have faith that those above you are making the best and most informed decisions they can, even though you will never understand the factors that went into such a decision.

Principals of instructional design Essay

Organizational strategy is concerned with vision goals and objectives of an organization. The task of an organization design is to look at the state of the business and to plan strategies organization that meets its needs. Managers of different organizations and companies should warm up to the advancing machinery analyze the situations of their organizations and see how the advancing technology would be of help when planning their strategy and making radical design changes to the organization. When creating a road map for the firm or company, the designer should put into consideration the vision of the company. Therefore, the plan that the designer comes up with should be in line with the vision of the organization. Other factors that the designers or managers of a company should think of before laying out a plan to change the organization and its structure are long term and short-term objectives of the organization and its goals (Brently, 2003). A goal is a general statement that is used to refer to the targets and aspirations that a company has and aims to accomplish. For these goals to be accomplished, determination and dedication to the work the employees do is highly recommended. My learning intervention is primarily about competence in the field of business. Competence has not been highly displayed in the business market and the intervention will be expected to instill real professionalism in these students once they graduate and are ready to venture into business. When the management of an organization decides to design strategies for their organizational it does not mean that, the organization was not strategized in the first place. It means that there is need to adjust to the changes that are happening daily in the global market. Starting the process of engineering again is all about main reformations of the organizations activities. It’s done to expand its structure when it comes to expenses incurred , the time the organization spends and how it meets the needs of the customers Repeated engineering of an organization means that the organization has to be redesigned from the beginning. The redesigning process starts with the most important processes. This saves a lot of time and costs that would have been incurred in the whole process compared to laying strategies when it is in its current structure. This will mean that major changes that are not very essential will have to be made which is far more expensive If a company had no existing departments, jobs and protocol, reengineering will involve design of an effective strategy that meets the objectives and accomplishes its goals. The process of reengineering begins when the designer’s are determined and put into consideration the needs of the customers. The company knows what is expected from it and develops a line up to cater for the clients or customers. Top management can create a competent team of people to design an organizational system that will achieve the laid strategy. Rethinking the organization is another factor to be considered. This is a process of Restructuring of the organization. Internal units under the management will be free to interrelate with each other and with the ecological forces. Some organizations display the traits of this management approach to organization design (Rodney, 1998). Managers in a global environment should consider what they have and do not have in common with other firms as well as the structural features of multinational organizations. More firms have made contact with the international arena and have found it essential to rethink the styles they came up with to help them adjust handle the cultural diversity for example, once a company has achieved a reasonable contact globally, it establishes an intercontinental distribution and this distribution is at the same organizational level as other major functional divisions. Learners will get to comprehend why technological and environmental changes are important in business and the effects that they have. They will be given insight on why changes in IT are happening so fast and extensively embraced. This will explain the reason why the relationship between the employees, allotment of information and harmonization of tasks need to be reviewed almost every day. Learners will understand why it is important to establish contacts and have good relation with the customers at the preliminary stage. They get to know how productivity is seen through involvement of people. Staying in touch with the customers is essential since it gives the designers ideas on what to consider as they design the strategies for a particular firm or organization. Learners will identify and explain dominant themes of current design strategies and their approaches. eg, universal approaches and contingency approaches. This is necessary because it helps the managers identify the best approach to use for their organization. The learner will explain how an organization is a system that is open and structured to incorporate two essential subsystems. The systems can be identified as the social and the technical subsystem (Maslow, 1998). Organizations are expected to lay strategies that take care of those in authority; they should also give an update of the relationships around the employees. The strategies are also supposed to cater for the training of interns and those already employed inspection, rewards and punishments. Learners will know what the task of management, which is to observe the environment and issue directions or orders on structures, rules and procedures. When teaching organizational strategies, a content outline and unit plan should be created. The content outline contains the topics that the tutor is supposed to cover in the entire course for example a topic on instructional design (Brently, 2003). The tutor explains the contents of the topic as an introduction at the beginning of the topic. This gives the learner an idea of what to expect in the course duration. The tutor assigns duration of time to each of the topics he intends to cover by the end of the course. He might decide to assign 4 weeks to the topic Principals of instructional design. He has estimated that by the end of the 4 weeks, the topic should have been completed and another one began. The relevance of the intervention and instruction is to help learners describe the general nature and extent of business and how global competition affects business operations and in general how to design strategies for the company or organization in order for the business to flourish. The intervention helps the students become competent in their different business fields. Therefore, the topics identified above all serve the purpose of instilling the relevant information for the intervention. The tutor is required to design a unit plan. It contains topics that will be taught, for example organizational design strategies. He should still give an introduction of the topic to the students (Maslow, 1998). The plan also contains time duration that each topic need to be completed. Again, it is an estimate and sometimes it extends but the tutor should try to keep time. It also contains room set up. That is the environment that the learning should take place in and its condition. The tutor should also identify the method of interaction. For example he might decide on small group discussions to give room for different opinions or to conduct a case study. The students can be asked to choose the people they want to work with. The materials for research or teaching are also included in the unit plan (Rodney, 1998). The materials could be slide’s, internet, resource books or journals. The teacher identifies the materials or media the students should use for a particular topic. The learning outcomes are not exceptional in a unit plan. This helps the tutor know if the objectives of the intervention have been accomplished. The tutor will explain if the topic teaches verbal, cognitive strategies, intellectual skills or attitude. For example, the topic Organizational strategies teach cognitive strategies and intellectual skills. With organizational designs in future (Brently, 2003). Taxononomy level is also included. The tutor states what domain the topic falls in. Cognitive, affective or psychomotor domain. A topic like steps to designing an organizational strategy falls in the affective domain. It involves making goals and attaining them. The tutor should include in the plan his plans for assessment. This may be a comprehensive evaluation at the end of the course. This provides the tutor with information on the effort put in the instruction and if the students achieved what they were supposed to achieve at the end of the course. The plan will have the main objective of the study, which in this case is to be competent in the business world.

2-DISCUSSION QUESTION Coursework Example | Topics and Well Written Essays - 250 words

2-DISCUSSION QUESTION - Coursework Example ning.† Although Maude has a constitutional right to park her car in place properly designated for her, she has no right parking her car in a place reserved for handicapped whether in hurry or not. Therefore, she is not respecting the rights of others i.e. the handicapped. However, from another perspective, I think Maude is acting ethically. Going by the definition of physical handicap, I think Maude is physically handicapped, given that she parks her car at this place whenever she is in a hurry implying loss of memory coordination and sensation. However, given that she has not been diagnosed with this condition, I can authoritatively conclude by saying that she is acting unethically. Ethical issues involving minors has become a contentious issue in the world today. An act can be described legal but unethical. Legally, the 16-year old girl should not be put on the pill, but what remains a puzzle is whether the doctor’s action is ethical or not. Under the policy statement about ethical issues involving children, the policy statement states that, drugs may affect children in a different way from adults (Watterberg et al., 2013). Parents have the responsibility of bringing up their children in an ethical manner; thus, from a religious perspective, the doctor should have denied the girl the accessibility to medical pill with or without the parents’ approval because this violates Christian beliefs. However, the law provides for confidentiality of the doctor-patient privacy and, therefore, a doctor should under no circumstance share any information of his or her patient with anyone be it a minor or an adult. However, the girl being a minor she is deemed n ot able to make an independent decision concerning her health status and, therefore, the doctor acted within ethical lines in contacting her

Principles and Practices of Effective Leadership (Apple Inc) Essay

Principles and Practices of Effective Leadership (Apple Inc). Leadership Portfolio - Essay Example Each leader adopts a unique approach and style, through the interplay of one’s traits, intelligence, behavioral set, authority, power, temperament and charisma. Within an institution, there develops an emphasis on implementing leadership skills and abilities that are relevant across the organization. This cultivates the ‘leadership style of the organization’. Let us delve in to an analysis on leadership at Apple Inc. (formerly  Apple Computer Inc.), an American  multinational corporation that designs, develops and sells  consumer electronics, computer hardware, software and personal computers. The powerful visionary, Steve Jobs, was the co-founder of Apple Inc. along with Steve Wozniak. They went on the establish Apple as one of the world’s giants, with an unconventional approach and leadership style that was starkly different from conventional business wisdom. The predominating leadership approach at Apple Inc. was that of ‘Transformational Lea dership’, wherein Steve Jobs (the leader),  identified the need for  change,  created  a vision amongst his people to enforce the change and  finally, ensured its enforcement with the  unfailing commitment  of the  members  of his company. (Bryant S., 2012)... At a review session, Jobs was quick to grab a ‘Magic Marker’ and draw a two-by-two grid on the board, labeling each quadrant sequentially as â€Å"Consumer†, â€Å"Pro.†, â€Å"Desktop† and â€Å"Portable†. He insisted that Apple focus on just four great products (one for each quadrant), cancelling all other products. Steve Jobs is known to have said to Walter Isaacson, â€Å"Deciding what not to do is as important as deciding what to do. â€Å"That’s true for companies, and it’s true for products.† (Issacson, 2012). The Apple Company under Steve Jobs, developed a ‘perfectionist style’ with an eye for great detail. The success of the company lay in the fact that Jobs recognized his own strengths and delegated areas suited to other people’s strengths, so that only the best product emerged from its shores. Steve Jobs was a driven leader and the products and services he directed his company to develop and commercialize changed the way many of us live, as well as the course of a diverse set of industries, including computing, publishing, movies, music and mobile telephony (Katzenbach, 2012). Undoubtedly, the success of Apple Computers under Steve Jobs stemmed from his creativity in decision-making, charismatic leadership and the ability to take risks in order to adapt to changing market conditions. As testimony to Apple’s creativity, Steve Jobs himself famously said â€Å"innovation distinguishes a leader and a follower†! Both, situational factors and the leadership approach of Steve Jobs contributed to Apple’s success. By selecting Steve Jobs to lead the company, Apple was not only able to improve its performance, but also position itself to take advantage of the opportunity

Case Study Example | Topics and Well Written Essays - 2000 words

Case Study Example What decisions does the firm face with continued growth? The company has to decide on how to expand the business but not to operate in their sub sites. The challenge in proceeding with this decision is the fact that finding new sand gravel sites in the new areas is hard because they are Scarce. The Company’s director Frank Wardlaw has found two sites at Celadon owned by the local council. However, they are leasing only one site hence the company has to decide which site to take. The first site, Bardon Farm, has sand and it is promising because of the development of Washington new town and also because in South Shields, the number of housing is increasing and therefore the market for sand is high. Cleadon Hill produces gravel and the positive side of this site is that it has a ready market where Tyneside Company can secure a four year contract with motorway contractors. The firm therefore has to decide which site to take. What are the risks associated with expansion in particul ar the operational risks John Hepple might, however, been justified by being against the expansion because of the operational risks that come with it. The one major risk is that the company might end up in debt thereby losing its property due to borrowing so as to finance the expansion. John Hepple, being the main shareholder, is against having new shareholders and hence that option of getting finances is out. The other operational risk is that the company has a lot of competitors whom it should keep in touch with to avoid being left behind. This will not be easy as the firm will be concentrating with expansion. Expansion also comes with a lot of work and everyone is working towards proving that they made the right decision (Sease & John, 1994). This may lead to the employees having a lot of pressure and their morale may be compromised. They may feel overworked and the firm may not be able to motivate them in the short run because all their finances will have been exhausted in the e xpansion. The firm also faces the risk of making losses if they are not able to attract new customers. The company however can deal with the risks by ensuring that the money they borrow will be paid within a certain period and still leave them profits. The board of directors has selected a committee that will establish the feasible project so as to expand it. The committee which consists of employees gives them an opportunity to choose what they feel they are capable of achieving and therefore doing away with the risk of losing employees due to pressure. The firm should do enough research to know what their new customers expect. This way they will have new customers and also be ahead of their competitors. Analyze the cash flow presentation. Identify any potential problems with the identification of the cash inflows and outflows The company has come up with a cash flow that shows how money will move in and out enabling them to know the rate of return of the project. The cash flow sho ws movement of cash operations that is the sales; there are also the cash flows from financing. The difference between the cash inflows and outflows gives the net cash flow. The Tyneside firm may have potential problems in identification of cash inflows and cash outflows. This problem arises when purchasing items with cash which is an inflow unlike when purchasing i Case Study Example | Topics and Well Written Essays - 750 words - 3 Case Study Example Some former Hooters waitresses have filed a class action lawsuit, alleging that the ambience that is deliberately created in â€Å"Hooters† restaurants exposes them to sexual harassment. The issue here is to decide what would be the right things for Hooters to do, and why? â€Å"Hooters† positions itself as a restaurant for the sporty and fun loving types and deliberately employs attractive waitresses to create an even livelier ambience. But this chain never serves hard liquor and behaves as a responsible corporate citizen by donating liberally to local and national charities and national and international sports events. It even donates substantially to Holy Family Lutheran Church. But it also hires and invites gorgeous women like Playboy Playmates if it feels that might increase its turnover. One must first ascertain what moral rights the aggrieved parties to a dispute have and then decide on a course of action that best honours those rights. Human beings have a fundamental moral right to choose what they would like to do with their lives and they cannot be manipulated to suit objectives of other persons. Further, every human being has a right to the truth and must have free access to information that might substantially affect the choices that have been done. In addition, every human being has a right to what has been agreed upon as a contract and also not to be harmed or injured. The other touchstone of judging whether or not an action is ethical or moral is to evaluate the extent to which such action fosters common good of the society. By common good it is meant certain social policies, systems, institutions and environments that are equally to everyone’s advantage. The other equally important criteria that any advice must fulfil in order to be considered as an ethically and morally sound advice is whether such an advice encourages action that would strengthen and spread moral virtues in a society. A judge

Effective Career Management and Planning and Who Is Responsible for Essay

Effective Career Management and Planning and Who Is Responsible for This - Essay Example Career management's main task is to maintain the careers of the employees who have been enrolled on the active roster of an enterprise or a company and thus bolster their careers in the light of growing trends, changing circumstances and problems that might arise from time to time. This also means that employees are better understood by the organizations not only with regards to their own individual standpoints but from the whole industry's stance as well. This can be a positive sign since people would trust the initiatives which are taken by the corporations and thus aspire to contribute in a better and more productive manner as and when the need arises. In fact, this will be a proactive step rather than the one that needs encouragement and a pat on the back every now and then. Proactive efforts would reap far better and more fruitful results than a company which just praises once an employee does something extraordinary. (Llewellyn, 2002) Career management is not a new field that c omes under the management of human resources in organizations rather it is one tenet which needs to be discussed at length as the same was missing in the past, as far as organizational ranks are concerned.Effective career management comes about with a desire to have personality assessments and then to follow them in line with the technological changes which come ahead in one's career pathway. Advances in different fields of technology have done a great deal to produce miraculous devices and solutions. In some circumstances, however, these advances have created problems for the elderly. More aggressive technology approaches are used to extend the life of the elderly. (Rothwell, 2005) On the whole, the elderly, as well as others, welcome that development - even if they fear some of its consequences. The planning phase within career management and eventually the progression comes about with a sense to 'do it right' and to set the ball rolling within the personality domains. Career mana gement from the perspective of an organization also becomes an interestingly debatable task - more so with the advent of the human resource management regimes. This department takes care of the issues that are encountered by the professionals while they are undergoing career progression, settling problems and a host of other aspects.

Market Analysis- Opening a Tapas Restaurant in Pearland Texas Research Proposal - 1

Market Analysis- Opening a Tapas Restaurant in Pearland Texas - Research Proposal Example â€Å"Pearland is on its way to becoming the next major employment center in the Houston region† (Living in Pearland par. 1). Thus, it transpires that the city offers a highly conducive environment for launching a new restaurant, which can operate well in this region due to several factors. The population growth in this town shows a high market potential of Tapas Restaurant. Pearland is near to Hobby Airport and therefore the restaurant can cater to tourists and business people who travel to this area. Pearland Park and restaurant is one of the main attractions of Pearland city. Besides, Pearland Art League can be another potential source of market for the restaurant as it invites several people round the year for many functions. These are the market potential in Pearland. The restaurant has competitors there such as Pear Tree, Santa Barbara Italian Restaurant and Busy Bee Cafà © etc. The potential target customer groups for Tapas Restaurant include the employees and visitors of Texas Medical Center, Johnson Space Center’s workers, visitors to Pearland Park and Hobby Airport etc. Besides, there are several well established families living in the area. Since there are no outlets of Tapas Restaurant in this region, Pearland City is a potential market for opening such a restaurant. This restaurant’s target customers are youth and upper middle class people. Target market identification involves the process of determining the group of potential clients from the inhabitants of a community, which may comprise several sections. Once this is done, the firm concerned has to make sure that they are in position of gratifying the desires and requirements of each section. Marketing aims, which add to the achievement of the general industry objectives should be recognized for all target markets. The objectives must be in quantitative language, should indicate the target market and must also point out the period within which the goals must be

Journal reflective Essay Example | Topics and Well Written Essays - 1000 words

Journal reflective - Essay Example Conceptually, these two aspects have brought a revolutionary paradigm in marketing that mainly focuses on having and taking care of the customers rather than merely attracting them. Notably, though, is the importance of these two elements in business today with respect to the customers and the progress of the organization in context. Delineating from their generality, value concept, and relationship marketing have several other constituents tied to them. Besides, myriad theories combine to link, separate and contextualize the value concept and relationship marketing to the prevailing business environment. Within the value concept, for instance, is the customer-perceived value, mathematically defined as the perceived benefits divided by the perceived sacrifice.3 The sacrifices, in this case, are the costs the customer has to incur during purchase such as purchase price and installation costs among others. To sum up about the value concept, it is very critical for any company aiming to launch competitive values to the clients to carefully analyze and understand the needs of the clients.4 It is the riskiest part of the value concept since the lack of such understanding may dilute customer loyalty. It may be a total waste of resources, and cause a ripple effect of not meeting the objectives of the company. In genera l, the value concept is directly proportional to relationship marketing.5 Arguably, reading this article is not only important to anyone aiming to start a business, but also to the established companies. Clearly, the impact of such reflection on professional learning and professional marketing skills cannot be overemphasized. As already asserted above, the reflection has a direct relationship with both professional learning and the real business environment. For one, it is through the reflection that a learner

Turning Point Of My Life Essay Example for Free

Turning Point Of My Life Essay The engines of the 747 jumbo passenger jet roared loudly in my ears with a resonance that said â€Å"There’s no turning back.†Ã‚   I tried to ignore this humming, chanting, vibrating message shaking my legs and rocking my spine.   I fumbled with the cool, silver metal of my seatbelt buckle and checked one more time that I was really locked in.   I felt the aircraft rolling left, then taxiing right, and I tried as best I could to believe it knew the best way to go.    I took Sonia’s slender hand in my own clammy palm without ever looking up.   In my mind I saw the historic monuments and pastoral countryside of France sweeping past, out of view, though I knew I was still safely on the runway.   I saw my mother and father, my lifelong friends.   And then my back pushed hard against the seat as the engines raged into a frenzy and the wheels of the airplane lost contact with the ground.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   As a small child in France I used to play with my best friend XXXX in the schoolyard.   We were equipped with arsenals of toy cars and trunks, ships and robots.   I always loved the airplanes best; I remember holding them as high as I could against the backdrop of the blue sky, my point of view convincing me I was among the clouds, thousands of feet above our little playground.   I would climb to the top of the slide and continue my flight, achieving the most spectacular heights with which no boy, anywhere, could compete.   I imagined flying away to parts of the world I didn’t yet have names for, exploring mountain peaks and silty ocean bottoms.   I ventured alone into the furthest reaches of the globe, a fearless pilot explorer.   As I sat now in the belly of a real life airplane, soaring off to meet my destiny, I hoped I was as brave now as I was back then.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   They told me lots of things about Washington, D.C.   They told me to be careful as the crime rate was high and I didn’t want to get shot.   They told me the Washington Monument was a sight to behold.   They told me Washington was where political deals are made that affect the entire planet.   They told me D.C. was the land of opportunity.   I couldn’t wait to get there and find out who was right and who was wrong.   I wondered how the Promised Land would compare with France, the only land I’d ever called home.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   I knew Sonia was excited.   We were like twins, she and I.   Same small home town, same field of study, same destination.   She displayed the kind of adventuresome free spirit I did as a little boy, and I admired her for it.   We were both giddy to move into our cozy new apartment together and finally begin a life together, on our own to make it or break it.   We were all starry eyes and heads full of possibility as we hurtled over the ocean toward the land they called America.   We grasped each others hands tighter as we told bad jokes and laughed nervous laughs about what awaited us when the wheels of our aircraft touched the ground.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Back in France, my brother Georges and I loved watching sports together on the weekends.   We’d argue over our favorite teams and cheer on the local favorites over lots of food and drinks.   We’d been close growing up and I knew I’d miss those weekend bonding sessions.   I wondered when and if Georges would get the chance to come to the States to see his brother, a big time Business major in Washington.    And what about mom and dad?   I knew they were at once sad and overjoyed that their little boy was rushing off to make something of himself, and I wondered which emotion won out.   I hoped, for their sake and mine, that they were happy in the knowledge that I was growing up alright.   As Sonia quietly sipped a complimentary diet soda, I could see in her eyes that she was having the same wistful thoughts of home.   I told her it was all going to be ok and that, hey, we would practically be neighbors with George W. Bush.   We both had a good laugh at that one.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   As I alternated between watching the second hand on my watch tick off the time and staring out over the billowing clouds below, I daydreamed of the future.   I saw our cozy apartment, furnished with a nice sofa and chairs, a television, and our very own bowls, plates, cups, and silverware.    I imagined us under a blanket on a frosty D.C. night, watching American sitcoms and eating take-out.   I saw us working feverishly behind computers and in libraries, expanding our minds and moving closer toward our goals.   We would hang out with our new American friends in American bars and drink American beer.   We would go see American rock concerts and joke about how Americans think we French folks are rude.   Maybe one day we’d get a dog or a cat.   The possibilities seemed fascinating and endless.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   As the plane made its final descent, my heart was in my throat.   â€Å"This is it,† the engines of the plane said.   Once again I checked my safety belt to make sure I was fastened in.   Though I loved to fly, the landing was always my favorite.   I loved seeing the expanse of a new city, laid out in miniature before my eyes.   I loved to watch as the tiny model world with me floating above it became the looming, real world with me in the middle.   Sonia and I smiled oversized, childlike smiles at each other as the wheels of the jet rubbed against the concrete landing strip, sending small puffs of up smoke into the air.   We bobbled and bumped along the jet way as the passengers stretched and gossiped amongst themselves until, finally, the plane came to a stop.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Sonia and I departed the plane, hand in hand, and breathed in the air of our new home.   The airport seemed to heave in and out with the swarms of people moving through it.   Momentarily, all thoughts of home, my childhood, and my future departed as I became intoxicated with the overwhelming here and now.   We stopped briefly for a greasy airport hamburger before hustling to collect our baggage and hail our first American cab to take us home.   Anxious, Sonia did a little dance next to her bags as I waited for the cabby to load our things into his bright yellow vehicle.   We closed the cab doors behind us with a bang and were on our way.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Sonia and I have been enjoying our new life in the States.   We finally got our things unpacked and situated in our cozy new apartment.   We do all of the things I’d imagined on that airplane, and then some.   In some ways life in a new country is like life on another planet, and Sonia and I enjoyed playing the extraterrestrials.   Each day at a shopping mall and each night at a club or a theater was a new adventure.   We were in uncharted territory and we wanted to map as much ground as we possibly could, drinking in the ups and downs of our newfound culture.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Of course, we became engrossed in our studies.   Though we are early on in our American education, I can sense the small milestones as we work our way along toward that fateful graduation day.   Until then, we enjoy our classmates and our professors and try to do the best we can with what we have.   We’re very lucky to be here, as so many people in the world never see the land beyond their hometown.   We’ve seen the lands beyond and the waters in between.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   As for my friends back home, I keep up with them via email and telephone.   I wonder how people must have gotten by without the wonders of the Internet.   I e-mail photos back home of Sonia and me at various landmarks and field questions about what it’s like living in Washington.   Of course, I inquire as to how my old pals are doing and try to keep up on the latest local gossip from home.   A couple of my friends have promised to come and visit, and I certainly hope they do.   Experiences like this are so much better when you can share them with people who really know you.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   And then there’s Georges.   We keep in touch the same way, and I keep him up to speed on American sports while he fills me in on French sports.   I’m trying to get him excited about American football, but I don’t know that I’m succeeding.   Sometimes we talk on the phone on during weekend sporting events and for awhile it is almost like we’re back home again, together.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Sonia and I are discovering what it’s like to live together as a couple.   We bicker about small and unimportant details like an old married couple, but we enjoy it and we’re enjoying our time together.   We’re beginning to learn what it’s like having to give in to each other’s wants and needs in order to keep each other happy.   We talk about the future, about next year, about what happens after graduation.   We enjoy making plans but are careful to also enjoy the present.   Someday when I’m an important business executive, I’ll look back at my time in college as the best time of my life.   I want to live life and remember as much of it as I can.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Of course I miss my family, my friends and my France.   Some things here will just never compare – I think most people feel that way about home.   Restaurants will never compare to my mother’s cooking and even my best American friends won’t remember the time I fell down on the playground and skinned my knee.   My time away from everybody has made me appreciate them all more and I look forward to the times when we get to talk.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Sometimes I think back to that time in the plane on the French runway.   I think about my sweaty palms and the roar of the engine and the tight seatbelt.   I think about my uncertainty towards leaving my home country, and I think about how well we’re adjusting so far.   I feel the same way when I think about my life and what my future holds – I hear the roaring jet engines telling me â€Å"This is it.†Ã‚   I guess all one can do is try their best and keep moving forward.   Stepping onto that airplane is the hardest part.   After that all you can do is sit back and enjoy the ride.

Total Knee Replacement Post Op Pain Management

Total Knee Replacement Post Op Pain Management To improve the quality and mobility of life, the most frequently used operative procedure is the total knee replacement. But it is necessary to administer the pain relief measures in the post operative period which would allow the ambulation and reduce the post operative complications. It is important to consider the pain relief options provided in the text with reference to the possible adverse affects in each case. Objective The main objective is the identification of the most suited method for the post operative pain control after the Total Knee Replacement Surgery. Methodology The random control trials executed on adult patients with the Total Knee Replacement Surgery was identified by going through the databases of MEDLINE, PUBMED, COCHRANE and CINAHL from the year 2000 to the present year. Results The patients involved in this study had pre operative and post operative osteoarthritis diagnosis. The continuous pain arising due to the arthritis can be eliminated by the total knee arthoplasty treatment. The use of femoral nerve blockade can be used to treat the pain after the total knee arthoplasty. Reduced oral opioid were taken in by the patients with primary, unilateral, noncemented total knee arthoplasty. These patients are also known to take less stool softener as a post operative measure and have increased mobilization. The patients poor health often resulted due to the obesity which led to a modifiable co-morbidity as was shown by the higher classification of the ASA. Conclusion Until now no adequate solution has been found to the pain after the Total Knee Replacement surgery. Although some consideration could be given to the combined femoral nerve block, the author however supports the use of multimodal approach in the control of postoperative pain in the TKR surgery. This method should be administered keeping in mind the clinical status of the individual patient, availability of skilled technicians and adequate equipment.Contents Page 1 Introduction Pain according to the International Association for the Study of Pain, has been described as an unpleasant emotional and a sensory experience that is often connected to an actual or a potential damage or is a sense that may be described in terms of that damage (Merskey, 1986). Although much advancement have been made in the study of mechanisms and their treatment, still they scientists have been unable to find the appropriate solution to postoperative pains (Joshi and Ogunnaike, 2005). If the inadequate methods of relieving pains are administered, then this may cause damage to the physiological and psychological workings and the patient may need more time to recover and return to the daily life (Gottschalk and Smith, 2001; Joshi and Ogunnaike, 2005). The most dreadful consequence can be death itself. In addition patients are complaining about the post operative symptoms such as pain which results due to the anesthesia or any surgical procedure. It is also an established fact that a postoperative pain treated inadequately can inculcate into a chronic pain which may be not diagnosed properly and will lead to its negligence (Joshi, and Ogunnaike, 2005). The health care costs and the resources are required more in these cases (Phillips, 2003). It is important that steps be taken to improve the control of preoperative pain which is a much better option and will lead to the reduction of post operative morbidity. This will therefore increase the standard of health associated quality of life and will also benefit the health sector economically. Theory of Pain The Gate Control Theory was established by Melzack and Wall (1965), to explain the differences in the perceptions of the similar stimuli. These scientists believed in the existence of some sort of a gate in the spinal cord that would open in specific situations and allow the passage of the nerve impulses linked with the pain stimulation which was then read by the brain as a sensation of pain. They also believed that certain psychological factors such as the anxiety would also affect the degree of the opening of the gate. Therefore in order to minimize the pain the theory was based on the idea of closing this gate. According to the Gate Theory, it was possible to control the transmission of the pain impulses through a gating mechanism present along the nervous system. The pulses can move in both the direction both up and down the nervous system. This means that the whole nervous system is involved in the perception of the pain response (Suza, 2007). Physiology of Pain The basic process of the pain transmission is Nociception. According to Loeser and Treede (2008), the Nociception is the neural process of encoding and the process of noxious stimuli. The mechanical, thermal or the chemical changes when surpasses the set limit, then they can be detected by the nociceptors or the pain receptors. The nociceptors transmit a signal along the spinal cord after its stimulation, to the brain which is then perceived by the brain as a sensation of pain (McCaffery and Pasero 1999). Pathophysiology of pain The sympathetic nervous system is activated by the stress responses in which the body is alerted to the existing harm. This denotes that the stress responses are a protective measure by nature. Through the stress responses the damages like blood loss is minimized as well as the perfusion to the vital organs will be maintained, healing will be enhanced and prevention to infections will also be carried out (Singh, 2003). But if the pain is prolonged then harmful consequences may be caused to the multiple systems of the body. A calculated amount of the hormones are released by the endocrine system which are responsible for the conversion process and the utilization of the carbohydrates, proteins and fats. Excessive amounts of these hormones are released by the endocrine system when the person is under stress. These hormones include Cortisol, Growth hormone, Adrenocorticotrophic hormone, Antidiuretic hormone, Catecholamine and Glucagon. Tachcardia, fever, shock, increased rate of respiration and some severe results leading to death may be produced by the combination of the inflammatory process, endocrine and the metabolic changes. The stress responses are prolonged by the pain and physical changes and may severely affect the recovery of the patient from the situation of trauma (McCaffery and Pasero, 1999). The sympathetic nerves system is activated as a response to the stress by the cardiovascular system. A number of affects are caused by the activation of the sympathetic nervous system in the post operative period, such as; increase in the heart rate, hypercoagulation due to the decrease in the fibrinolysis, blood pressure, oxygen demand and a cardiac workload. Major impacts of the hypercoagulation may be seen on the morbidity and the mortality as these may be connected to the infarction, irregular angina and myocardial ischemia. The risks of pulmonary embolism may be increased due to the deep venous thrombosis (DVT) which is generally associated with the surgical procedures and an absence in the movement postoperatively. The respiratory system affects of the severe pain can be calculated in terms of the high inspiratory and expiratory residual capacity, tidal volumes and the alveolar ventilation. If the controlling measures applied to the postoperative pain are not adequate then the adverse respiratory affects can convert to severe pulmonary complications in the form of atelectasis and pneumonia (McCaffery and Pasero, 1999). The urine outputs, electrolyte balance, other fluids are regulated by the hormones in the Genitourinary System. These hormones also control the blood volume and the pressure. These hormones may include ADH, cortisol, angiotensin II, catecholamine, prostaglandins and aldosterone. If the pain is not relieved then it may lead to the excess release of the hormones which can cause the water and the sodium ions to be retained, the functional extracellular fluids are decreased with the fluids being moved to the intracellular compartments and the excess excretion of the potassium ions. Among the harmful effects are: decrease in the urinary output, increase in the cardiac workload, urine retained, hypokalemia, hypertension and the overloading of the fluids (McCaffery and Pasero, 1999). The activity of the sympathetic nervous system is increased due to the stress responses which affect the Gastrointestinal System, increase in the smooth muscle sphincter tone, intestinal secretion and the decrease in the gastric disposal and intestinal motility. These may lead to the gastrointestinal function to be temporarily impaired (McCaffery and Pasero, 1999). The pain in the Musculoskeletal System may lead to the impairment of the muscle function, muscle spasm, immobility and fatigue. The short and the long term recovery can be affected by the inadequate control of the pain after the execution of an orthopedic surgery as this may create interference in the patients performance of the physical therapy exercises (Choy, Bandar, Scott and Dockets, 2010). The hospital stay for the patient may be prolonged as a result. The time duration spent by the patient in the hospital indicates the patients satisfaction level. Patients who had a short stay were found to be more satisfied as compared to those with longer hospital stay. The Immune function can be suppressed by the pain (page 2000) which will make the patient more vulnerable to postoperative infections such as pneumonia, sepsis and the wound infection. The severe acute pain or the pain which is prolonged can affect the Cognitive function which will make the patient to undergo some behavioral changes such as the increased sensitivity to the external stimuli like light and sound. Individuals may react by withdrawing themselves form interpersonal interactions and an increased indulgence in ones self concern (NHMRC, 2005). If the pain is not relieved the patient may experience a loss of control over the environment such as the expression of anger and resentment which may make the patient believe that the treatment is being delayed (Joshi and Ogunnaike, 2005). Postoperative pain control The surgical pain should be appropriately managed owing to the negative effects that it has on the physical and the psychological system of the postoperative patient. The following methods have been applied in the Total Knee Surgery in the practice area of the author in the area of orthopedic surgery: Systemic Opioids The treatment of moderate and acute pain can be done through opioids which is still the main systemic analgesia. Titration is needed to estimate the individual needs as the opioids requirements differs from one patient to another with respect to dosage. The most effective pain relievers are the opioids but they are generally not desired by the patients or the doctors due to the wide ranging adverse effects (NHMRC, 2005). Paracetamol To treat the post operative pain, paracetamol was introduced as an analgesic and antipyretic. The use of opioid was reduced by 20-30% by the usage of paracetamol and the level of patient satisfaction was also increased. The postoperative pains are also affectively dealt with the combination of Non-Steroidal Anti-inflammatory drugs (NSAIDs) and the opioids. The NSAIDs are effective analgesics, anti-inflammatory drugs and antipyretics. The NSAIDs are also helpful in reducing the usage of opioid, but the adverse effects associated with this drug has made the clinicians extra careful when using it. The method in which the patient can administer the analgesics as needed is referred to as the Patient Controlled Analgesia (PCA). Although this term may be more frequently associated with the programmable infusion pumps that administer the dose for the opioid medication intravenously (Morgan, et al. 2006). The cumulative doses of the drugs are decreased in comparison to the continuous epidural infusion by the usage of Patient Controlled Epidural Analgesia which contains Bupivacaine and Fentanyl. This may be done without any difference seen in the side effects or the relief of pain. The duration of the postoperative analgesia is extended beyond the duration which is generally available in a single injection by the help of Continuous Peripheral Nerve Blockade (CFNB). The technique utilized in the nerve location, the typology of the continuous catheter, local anesthesia, equipment and the management is some of the technical issues that are brought under consideration. The CFNB is sometimes referred to as the 3-in-1 due to the triple benefits that it offers as when it the catheter is positioned in the femoral nerve sheath, it will allow the penetration of the local anesthesia to the lateral femoral cutaneous, the obturator nerve and the femoral nerve block (NHMRC, 2005). Total Knee Replacement (TKR) The patient suffering from acute pain and unstable knees, in order to gain a pain relief and a functional movement, requires a total Knee replacement surgery. Prophylaxis and early mobilization can reduce the complications and morbidity caused after the surgical procedures. Prophylaxis According to Palmer (2010), in the absence of prophylaxis there was an occurrence of 40-88% of deep venous thrombosis (DVT) after the TKR. According to Palmer several methods can be applied to reduce these risks such as low dose of warfarin, mechanical compression stockings, heparin of low molecular weight and aspirin. Mobilization A rapid recovery to the normal functions after surgery can be done through postoperative mobilization. If the postoperative pain is not relieved then it will lead to late mobilization which will increase the DVT risks, chest infection and pulmonary embolism. If the chest infection is concurred, then the static secretions will lead to atelectasis and pneumonia (Bone and Joint, 2009). 3 Methods The method of study was primarily based on the extensive literature review of the publications which were related to the management of postoperative pains in adults who have undergone Total Knee Replacement Surgery. The method was more preferred by the author due to limited clinical access to the patients as the author is an international student. This method was also chosen under the light of the statement by Aveyard (2007), who said that the literature review is able to provide a complete picture and helps in forming a systematic approach towards the studys answer. Therefore the study will include as many options available from the literature review as possible. Search strategy The Cardiff Universitys electronic database was used as the source to gain data on the most effective method used in the post operative pain control after the Total Knee Replacement Surgery. The search gave 246 hits with the keywords used such as Pain, Analgesia, Anesthesia, postoperative and Knee. Among these results the author selected the most relevant options with the help of Medline Ovid. The search was limited to the English language due to convenience in understanding this language as compared to the others and included results from the year 2000 to the present. The appendix 1 shows the details of the research strategy. Scope of the study The inclusion of the data in the study was based on adult human beings and total knee replacement surgery. The pediatric and other surgical specialties were not included in the research as was the study involving non human subjects. Data collection The MEDLINE, PUBMED, COCHRANE and CINAHL were the primary source of information. The Critical Appraisal Skills Programme criteria were used in the judging of the key methodological points considered in the Randomised Control Trials (PHRU, 2006). Data analysis In the published materials, broad themes were identified and studied with the most common and frequently used methods of pain relief resulting for the Total Knee Replacement Surgery were compared and analyzed with each other. The adverse effects of these methods were also considered in the analysis. The results were analyzed under the CASP (PHRU, 2006) criteria which was developed by the Center of Evidence based Medicine (CEBM, 2011). The appendix 2 shows the appraisal sheet. 3 Results (Review of the literature) A double blinded Randomized Controlled Trial was conducted by Kardash et al (2007), for the comparative analysis of the obturator with the femoral nerve block used for the analgesia after the Total Knee Replacement surgery. This was done by using at the surgerys end the spinal anesthesia with the femoral, obutrator or the placebo nerve block. The study consisted of 60 patients who were divided in treatment groups of varying sizes. The participants and the collectors were not aware of this allocation at all. All the patients were present in the study except for one patient who was removed from the study due to the confusion of the patient in the recovery room postoperatively. The patients were given a follow up after 48 hours of post surgery. The pain scores were found to be lowered after the femoral nerve block as compared to the obturator nerve block. But no difference was found in the groups after 48 hours related to pain or baseline among the groups. There was an absence of a sign ificant difference between the groups with the pain score of p=0.03 as an option. This would favor mobilization of the femoral block over the obturator block. The data is widely represented as shown by the demographics of the total knee replacement population. The findings could not be generalized owing to the small size of the groups. A prospective randomized placebo controlled single blind study was executed by Macalou (2004). The assigning of the patients into three groups was done randomly through envelops given to the patients. A femoral nerve block (FNB) was given to group 1 while combined and selective obturator nerve block, FNB=33 was given to the group 2. The group 3 was given the placebo FNB (n=28) with a total of 90 patients enrolled in the study. The three groups demonstrated no significant demographic differences. All the participants were present in the study without any dropouts and there was no failure of the block experienced which makes the study even more valid. In the first 6 hours the patients were monitored postoperative. The administration of the Patient Controlled Analgesia was initiated post anesthesia without the recording of any symptoms of pain in the first 6 hours. The study follow ups are from 24 to 48hours which means that the duration of the study of 6 hours is not sufficient to obtain any conclusions. 3 tables and 1 graph presented the study. The results obtained in the first 6 hours after the surgery showed the morphine boluses given through the PCA were consumed in a lesser number in group 2 as compared to the group 1 and 3 (P0.05). The ITM group showed an increase in the occurrence of nausea, pruritus and vomiting. About 20% of the patients in the ITM group in the follow up satisfactory survey rated their anesthetic experience as not satisfactory. These were considered in comparison with none in the FNB group (P=0.035). The validity and reliability of the study was enhanced by the reporting of the P value and the confidence interval. Equal amounts of the postoperative analgesia were experienced but the fewer side effects were seen in the FNB group such as nausea, itching and vomiting. Less level of satisfaction was observed among patients receiving T morphine. However the interventions were not sufficient to provide the completed postoperative analgesia. A randomized controlled trial was conducted by Davies in 2004, in which the 60 patients who underwent unilateral primary total knee replacement surgery were included in one of the two study groups. The continuous epidural analgesia was given to the group 1 until a single shot combined with sciatic plus femoral which is available in 3 in 1 combined block. The research used a random number generator, Arcus Quickstat version 1.0, to divide the participants in groups in which a third party would store the codes in sealed and opaque envelopes which would reduce the chances of bias (Parahoo, 2006). The exclusion of the patients was done on the following basis: local anesthesia, ASA>3, neuraxial blockage or the use of tourniquet, contraindications to use the non steroidal anti inflammatory drugs, pain poly analgesia. The criteria used for the exclusion seemed to be correct. All the participants were present in the study and in the conclusion. The failure to locate the epidural space led to the exclusion of one patient. After the exclusion the analysis was done but no difference in the results were seen in the analysis on an intention to treat the basis. The data collection was done in a similar manner and the follow up was carried out. A performance bias was created by the inconsistencies. The analysis of the patients was done for the pain assessment after 48 hours postoperatively with the use of a visual analog VAS. The power analysis was used to determine the sample size, obtained from a lower limb neural block study which showed the 10mm VAS difference. A risk of 0.05 was obtained in group A and a risk of 0.2 was obtained in group B. a minimum of 24 patients would be sufficient for the study. In each group 30 patients were however recruited to make up for the incomplete data collected and to make sure that the validity was ensured. 3 tables and 3 graphs were used to demonstrate the results. An absence of a statistical difference between the two groups was seen in the two groups for the block insertion time (P=0.92). The dose given for the fentanyl was to be same. In both the groups the score for the pain was higher than 24 and 48 hours. A greater number of the patients were found in the epidural group with the completed recovery of the analgesia. There was no pain reported in the 0.23 of 39 patients when a movement was attempted as compared to the 16 out of 30 patients form the block group. The scores of the level of satisfaction were found to be high in both the groups with an increased tendency of the statistical significance which was found to favor the block group at 48 hours. The validity of the study was increased with the discussion of the P value and the confidence interval. A practical alternative to the epidural analgesia was offered by the combined block for the total knee replacements. The results can be applied to the clinical setting.

Causes, Symptoms and Treatments of Anaemia

Causes, Symptoms and Treatments of Anaemia 1. Introduction Anaemia is a syndrome characterised by a lack of healthy red blood cells or haemoglobin deficiency in the red blood cells, resulting in inadequate oxygen supply to the tissues. The condition can be temporary, long-term or chronic, and of mild to severe intensity. There are many forms and causes of anaemia. Normal blood consists of three types of blood cells: white blood cells (leucocytes), platelets and red blood cells (erythrocytes). The first generation of erythrocyte precursors in the developing foetus are produced in the yolk sac. They are carried to the developing liver by the blood where they form mature red blood cells that are required to meet the metabolic needs of the foetus. Until the 18th week of gestation, erythrocytes are produced only by liver after which the production shifts to the spleen and the bone marrow. The life of a red blood cell is about 127 days or 4 months (Shemin and Rittenberg, 1946; Kohgo et al., 2008). The main causes of anaemia are blood loss, product ion of too few red blood cells by the bone marrow or a rapid destruction of cells.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Haemoglobin, a protein, present in the red blood cells is involved in the transport of oxygen from the lungs to all the other organs and tissues of the body. Iron is an important constituent of the haemoglobin protein structure which is intimately involved in the transport of oxygen. Anaemia is generally defined as a lower than normal haemoglobin concentration. The normal blood haemoglobin concentration is dependent on age and sex, and, according to the World Health Organisation (WHO) Expert Committee Report, anaemia results when the blood concentration of haemoglobin falls below 130 g/L in men or 120 g/L in non-pregnant women (WHO, 1968). However, the reference range of haemoglobin concentration in blood could vary depending on the ethnicity, age, sex, environmental conditions and food habits of the population analysed. According to Beutler and Warren (2006), more reasonable benchmarks for anaemia are 137 g/L for white men aged between 20 and 60 years and 132 g/L for older men. The value for women of all ages would be 122 g/L. Also, the lower limit of normal of haemoglobin concentrations of African Americans are appreciably lower than that of Caucasians (Beutler and Warren, 2006).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Besides the well recognised iron deficiency anaemia, several inherited anaemias are also known. These are mostly haemoglobinopathies. Adult haemoglobin is a tetrameric haeme-protein. Abnormalities of beta-chain or alpha-chain produce the various medically significant haemoglobinopathies. The variations in amino acid composition induced genetically impart marked differences in the oxygen carrying properties of haemoglobin. Mutations in the haemoglobin genes cause disorders that are qualitative abnormalities in the synthesis of haemoglobin (e.g., sickle cell disease) and some that are quantitative abnormalities that pertain to the rate of haemoglobin synthesis (e.g., the thalassemias) (Weatherall., 1969). In SCD, the missense mutation in the ÃŽ ²-globin gene causes the disorder. The mutation causing sickle cell anemia is a single nucleotide substitution (A to T) in the codon for amino acid 6. The substitution converts a glutamic acid codon (GAG) to a valine codon (GTG). The form of haemoglobin in persons with sickle cell anemia is referred to as HbS. Also, the valine for glutamic acid replacement causes the haemoglobin tetramers to aggregate into arrays upon deoxygenation in the tissues. This aggregation leads to deformation of the red blood cell making it relatively inflexible and restrict its movement in the capillary beds. Repeated cycles of oxygenation and deoxygenation lead to irreversible sickling and clogging of the fine capillaries. Incessant clogging of the capillary beds damages the kidneys, heart and lungs while the constant destruction of the sickled red blood cells triggers chronic anaemia and episodes of hyperbilirubinaemia.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Fanconi anaemia (FA) is an autosomal recessive condition, and the most common type of inherited bone marrow failure syndrome. The clinical features of FA are haematological with aplastic anaemia, myelodysplastic syndrome (MDS), and acute myeloid leukaemia (AML) being increasingly present in homozygotes (Tischkowitz and Hodgson, 2003). Cooleys anaemia is yet another disorder caused by a defect in haemoglobin synthesis.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Autoimmune haemolytic anaemia is a syndrome in which individuals produce antibodies directed against one of their own erythrocyte membrane antigens. The condition results in diminished haemoglobin concentrations on account of shortened red blood cell lifespan (Sokol et al., 1992).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Megaloblastic anaemia is a blood disorder in which anaemia occurs with erythrocytes which are larger in size than normal. The disorder is usually associated with a deficiency of vitamin B12 or folic acid . It can also be caused by alcohol abuse, drugs that impact DNA such as anti-cancer drugs, leukaemia, and certain inherited disorders among others (Dugdale, 2008).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Malaria causes increased deformability of vivax-infected red blood cells (Anstey et al., 2009). Malarial anaemia occurs due to lysis of parasite-infected and non-parasitised erythroblasts as also by the effect of parasite products on erythropoiesis (Ru et al., 2009).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Large amounts of iron are needed for haemoglobin synthesis by erythroblasts in the bone marrow. Transferrin receptor 1 (TfR1) expressed highly in erythroblasts plays an important role in extracellular iron uptake (Kohgo et al., 2008). Inside the erythroblasts, iron transported into the mitochondria gets incorporated into the haeme ring in a multistep pathway. Genetic abnormalities in this pathway cause the phenotype of ringed sideroblastic anemias (Fleming, 2002). The sideroblastic anemias are a heterogeneous group of acquired and inherited bone marrow disorders, characterised by mitochondrial iron overload in developing red blood cells. These conditions are diagnosed by the presence of pathologic iron deposits in erythroblast mitochondria (Bottomley, 2006).    2. Classification of anaemia Anaemia can be generally classified based on the morphology of the red blood cells, the pathogenic spectra or clinical presentation (Chulilla et al., 2009). The morphological classification is based on mean corpuscular volume (MCV) and comprises of microcytic, macrocytic and normocytic anaemia.   Ã‚  Ã‚  Ã‚  Ã‚  (a) Microcytic anaemia refers to the presence of RBCs smaller than normal volume, the reduced MCV ( 15 would probably indicate IDA (Chulilla et al., 2009).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  In macrocytic anaemia, erythrocytes are larger (MCV > 98 fL) than their normal volume (MCV = 82-98 fL). Vitamin B12 deficiency leads to delayed DNA synthesis in rapidly growing hematopoietic cells, and can result in macrocytic anemia. Drugs that interfere with nucleic acid metabolism, such as.hydroxyurea increases MCV (> 110 fL) while alcohol induces a moderate macrocytosis (100-110 fL). In the initial stage, most anaemias are normocytic. The causes of normocytic anaemia are nutritional deficiency, renal failure and haemolytic anemia (Tefferi, 2003). The most common normocytic anaemia in adults is anaemia of chronic disease (ACD) (Krantz, 1994). Common childhood normocytic anaemias are, besides iron deficiency anaemia, those due to acute bleeding, sickle cell anemia, red blood cell membrane disorders and current or recent infections especially in the very young (Bessman et al., 1983). Homozygous sickle cell disease is the most common cause of h aemolytic normocytic anemias in children (Weatherall DJ, 1997a).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  In practice, the morphological classification is quicker and therefore, more useful as a diagnostic tool. Besides, MCV is also closely linked to mean corpuscular haemoglobin (MCH), which denotes mean haemoglobin per erythrocyte expressed in picograms (Chulilla et al., 2009). Thus, MCV and MCH decrease simultaneously in microcytic, hypochromic anemia and increase together in macrocytic, hyperchromic anemia.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Pathogenic classification of anaemia is based on the production pattern of RBC: whether anaemia is due to inadequate production or loss of erythrocytes caused by bleeding or haemolysis. This approach is useful in those cases where MCV is normal. Pathogenic classification is also essential for proper recognition of the mechanisms involved in the genesis of anaemia. Based on the pathogenic mechanisms, anaemia is further divided into two types namely, (i) hypo-regenerative in which the bone marrow production of erythrocytes is decreased because of impaired function, decreased number of precursor cells, reduced bone marrow infiltration, or lack of nutrients; and (ii) regenerative: when bone marrow upregulates the production of erythrocytes in response to the low erythrocyte mass (Chulilla et al., 2009). This is typified by increased generation of erythropoietin in response to lowered haemoglobin concentration, and also reflects a loss of erythrocyt es, due to bleeding or haemolysis. The reticulocyte count is typically higher.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Sickle cell disease is characterised by sickled red cells.   The first report of SCD was published a century ago noting the presence of peculiar elongated cells in blood by James Herrick, an American physician (1910). Pauling et al. (1949) described it as a molecular disease. The molecular nature of sickle haemoglobin (Hb S) in which valine is substituted for glutamic acid at the sixth amino acid position in the beta globin gene reduces the solubility of Hb, causing red cells to sickle (Fig. 1). Sickling of cells occurs at first reversibly, then finally as a state of permanent distortion, when cells containing HbS and inadequate amounts of other haemoglobins including foetal haemoglobin, which retards sickling, become deoxygenated (Bunn, 1997). The abnormal red cells break down, leading to anaemia, and clog blood vessels with aggregates, leading to recurrent episodes of severe pain and multiorgan ischaemic damage (Creary et al., 2007). The high levels of inflammatory cytokines in SCD may promote retention of iron by macrophage/reticuloendothelial cells and/or renal cells. SCD care commonly depends on transfusion that results in iron overload (Walter et al., 2009). 3. Pathogenesis of anaemia Anaemia is a symptom , or a syndrome, and not a disease (Chulilla et al., 2009). Several types of anaemia have been recognised, the pathogenesis of each being unique. Iron deficiency anaemia (IDA) is the most common type of anaemia due to nutritional causes encountered worldwide (Killip et al., 2008). Iron is one of the essential micronutrients required for normal erythropoietic function While the causes of iron deficiency vary significantly depending on chronological age and gender, IDA can reduce work capacity in adults (Haas Brownlie, 2001) and affect motor and mental development in children (Halterman et al., 2001). The metabolism of iron is uniquely controlled by absorption rather than excretion (Siah et al., 2006). Iron absorption typically occurring in the duodenum accounts for only 5 to 10 per cent of the amount ingested in homoeostatis. The value decreases further under conditions of iron overload, and increases up to fivefold under conditions of iron depletion (Killip et al., 2008). Iron is ingested as haem iron (10%) present in meat, and as non-haem ionic form iron (90%) found in plant and dairy products. In the absence of a regulated excretion of iron through the liver or kidneys, the only way iron is lost from the body is through bleeding and sloughing of cells. Thus, men and non-menstruating women lose about 1 mg of iron per day while menstruating women could normally lose up to 1.025 mg of iron per day (Killip et al., 2008). The requirements for erythropoiesis   which are typically 20-30 mg/day   are dependent on the internal turnover of iron (Munoz et al., 2009) For example, the amount of iron required for daily production of 300 billion RBCs (20-30 mg) is provided mostly by recycling iron by macrophages (Andrews, 1999).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Iron deficiency occurs when the metabolic demand for iron exceeds the amount available for absorption through consumption. Deficiency of nutritional intake of iron is important, while abnormal iron absorption due to hereditary or acquired iron-refractory iron deficiency anemia (IRIDA) is another important cause of unexplained iron deficiency. However, IDA is commonly attributed to blood loss e.g., physiological losses in women of reproductive age. It might also represent occult bleeding from the gastrointestinal (GI) tract generally indicative of malignancy (Hershko and Skikne, 2009).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Iron absorption and loss play an important role in the pathogenesis and management of IDA. Human iron disorders are necessarily disorders of iron balance or iron distribution. Iron homeostasis involves accurate control of intestinal iron absorption, efficient utilisation of iron for erythropoiesis, proper recycling of iron from senescent erythrocytes, and regulated storage of iron by hepatocytes and macrophages (Andrews, 2008). Iron deficiency is largely acquired, resulting from blood loss (e.g., from intestinal parasitosis), from inadequate dietary iron intake, or both. Infections, for example, with H pylori, can lead to profound iron deficiency anemia without significant bleeding. Genetic defects can cause iron deficiency anaemia. Mutations in the genes encoding DMT1 (SLC11A2) and glutaredoxin 5 (GLRX5) lead to autosomal recessive hypochromic, microcytic anaemia (Mims et al., 2005). Transferrin is a protein that keeps iron nonreactive in the circulation, and delivers iron to cells possessing specific transferrin receptors such as TFR1 which is found in largest amounts on erythroid precursors. Mutations in the TF gene leading to deficiency of serum transferrin causes disruption in the transfer of iron to erythroid precursors thereby producing an enormous increase in intestinal iron absorption and consequent tissue iron deposition (Beutler et al., 2000). Quigley et al. (2004) found a haem exporter, FLVCR, which appears to be necessary for normal erythroid development. Inactivation of FLVCR gene after birth in mice led to severe macrocytic anaemia, indicating haem export to be important for normal erythropoiesis.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  The anaemia of chronic disease (ACD) found in patients with chronic infectious, inflammatory, and neoplastic disorders is the second most frequently encountered anaemia after iron-deficiency anaemia. It is most often a normochromic, normocytic anaemia that is primarily caused by an inadequate production of red cells, with low reticulocyte production (Krantz, 1994). The pathogenesis of ACD is unequivocally linked to increased production of the cytokines including tumour necrosis factor, interleukin-1, and the interferons that mediate the immune or inflammatory response. The various processes leading to the development of ACD such as reduced life span of red cells, diminished erythropoietin effect on anaemia, insufficient erythroid colony formation in response to erythropoietin, and impaired bioavailability of reticuloendothelial iron stores appear to be caused by inflammatory cytokines (Means, 1996;2003). Although iron metabolism is characterist ically impaired in ACD, it may not play a key role in the pathogenesis of ACD (Spivak, 2002). Neither is the lack of available iron central to the pathogenesis of the syndrome, according to Spivak (2002), who found reduced iron absorption and decreased erythroblast transferrin-receptor expression to be the result of impaired erythropoietin production and inhibition of its activity by cytokines. However, reduced erythropoietin activity, mostly from reduced production, plays a pivotal role in the pathogenesis of ACD observed in systemic autoimmune diseases (Bertero and Caligaris-Cappio, 1997). Indeed, iron metabolism as well as nitric oxide (NO), which contributes to the regulation of iron cellular metabolism are involved in the pathogenesis of ACD in systemic autoimmune disorders. Inflammatory mediators, particularly the cytokines, are important factors involved in the pathogenesis of the anaemia of chronic disease, as seen in rheumatoid arthritis anaemia (Baer et al., 1990), the cyt okines causing impairment of erythroid progenitor growth and haemoglobin production in developing erythrocytes.     Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Anaemia is also commonly found in cases of congestive heart failure (CHF), again caused by excessive cytokine production leading to reduced erythropoietin secretion, interference with erythropoietin activity in the bone marrow and reduced iron supply to the bone marrow (Silverberg et al., 2004). However, in the presence of chronic kidney insufficiency, abnormal erythropoietin production in the kidney plays a role in the pathogenesis of anaemia in CHF.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  The myelodysplastic syndromes (MDS) are common haematological malignancies affecting mostly the elderly as age-related telomere shortening enhances genomic instability (Rosenfeld and List, 2000). Radiation, smoking and exposure to toxic compounds e.g., pesticides, organic chemicals and heavy metals, are factors promoting the onset of MDS via damage caused to progenitor cells, and, thereby, inducing immune suppression of progenitor cell growth and maturation. TNF- and other pro-apoptotic cytokines could play a central role in the impaired haematopoiesis of MDS (Rosenfeld and List, 2000). Premature intramedullary cell death brought about by excessive apoptosis is another important pathogenetic mechanism in MDS (Aul et al., 1998).     Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Sickle cell disease (SCD) arising from a point mutation in the ÃŽ ²-globin gene and leading to the expression of haemoglobin S (HbS) is the most common monogenetic disorder worldwide. Chronic intravascular haemolysis and anaemia are some important characteristics of SCD. Intravascular haemolysis causes endothelial dysfunction marked by reduced nitric oxide (NO) bioavailability and NO resistance, leading to acute vasoconstriction and, subsequently, pulmonary hypertension (Gladwin and Kato, 2005).    However, a feature that differentiates SCD from other chronic haemolytic syndromes is the persistent and intense inflammatory condition present in SCD. The primary pathogenetic event in SCD is the intracellular polymerisation or gelation of deoxygenated HbS leading to rigidity in erythrocytes (Wun, 2001). The deformation of erythrocytes containing HbS is dependent on the concentration of haemoglobin in the deoxy conformation (Rodgers et al., 1985). It has been demonstrated that sickle monocytes are activated which, in turn, activate endothelial cells and cause vascular inflammation. The vaso-occlusive processes in SCD involve inflammatory and adhesion molecules such as the cell adhesion molecules (CAM family), which play a role in the firm adhesion of reticulocytes and leukocytes to endothelial cells, and the selectins, which play a role in leukocyte and platelet rolling on the vascular wall (Connes et al., 2008). Thus, inflammation, leucocyte adhesion to vascular endothelium, and subsequent endothelial injury are other crucial factors contributing to the pathogenesis of SCD (Jison et al., 2004). 4. Current therapies for clinical management of sickle cell diseaseincludingacritical appraisal of transfusion Between 1973 and 2003, the average life expectancy of a patient with SCD increased dramatically from a mere 14 years to 50 years thanks to the development of comprehensive care models and painstaking research efforts in both basic sciences especially molecular and genetic studies, and clinical aspects of SCD (Claster and Vichinsky, 2003). The clinical manifestations of SCD are highly variable. Both the phenotypic expression and intensity of the syndrome are vastly different among patients and also vary longitudinally within the same patient (Ballas, 1998). New pathophysiological insights available have enabled treatments to be developed for the recognised haematologic and nonhaematologic abnormalities in SCD (Claster and Vichinsky, 2003). The main goals of SCD treatment are symptom alleviation, crises avoidance and effective management of disease complications. The strategy adopted is primarily palliative in nature, and consists of supportive, symptomatic and preventative approaches to therapy. Symptomatic management includes pain mitigation, management of vasoocclusive crisis, improving chronic haemolytic anaemia, treatment of organ failure associated with the disease, and detection and treatment of pulmonary hypertension (Distenfeld and Woermann, 2009). The preventative strategies include use of prophylactic antibiotics (e.g., penicillin) in children, prophylactic blood transfusion for prevention of stroke in patients especially young children who are at a very high risk of stroke, and treatment with hydroxyurea of patients experiencing frequent acute painful episodes (Ballas, 2002). Currently, curative therapy for sickle cell anaemia is only available through bone marrow and stem cell transplantation. Hematopoietic cell transplantation using stem cells from a matched sibling donor has yielded excellent results in paediatric patients (Krishnamurti, 2007). Curative gene therapy is still at the exploratory stage (Ballas, 2002). Current and potential therapies The potential treatment strategies basically target cellular dehydration, sickle haemoglobin concentrations, endothelial dysfunction, and abnormal coagulation regulation (Claster and Vichinsky, 2003). HbS concentrations are essentially tackled through transfusions while approaches to reduce HbS polymerisation which is the main mechanism for the development of vaso-occlusion include (a) increasing foetal haemoglobin (HbF) concentration using hydroxyurea (Fig. 2), butyrate, or erythropoietin, and (b) preventing sickle cell dehydration using Clotrimazole (Fig. 3) or Mg2+pidolate. Hydroxyurea therapy increases the production of HbF in patients with sickle cell anaemia, and, thereby, inhibits the polymerisation of HbS and alleviates both the haemolytic and vaso-occlusive manifestations of the disease (Goldberg et al., 1990). Recombinant erythropoietin also increases the number of reticulocytes with HbF. Additionally, it has been observed that administration of intravenous recombinant eryt hropoietin with iron supplementation alternating with hydroxyurea enhances HbF levels more than hydroxyurea alone (Rodgers et al., 1993). As SCD is essentially characterized by an abnormal state of endothelial cell activation   that is, a state of inflammation, a pharmacologic approach to inhibit endothelial cell activation has proved clinically beneficial (Hebbel and Vercellotti, 1997). Thus, administration of sulfasalazine which is a powerful inhibitor of activation of nuclear factor (NF)-B, the transcription factor promoting expression of genes for a number of pro-adhesive and procoagulant molecules on endothelium to humans has been found to provide transcriptional regulation of SCD at the endothelium level (Solovey et al., 2001). Red blood cell transfusion : a critical appraisal A key therapy that is applied regularly in the clinical management of patients with SCD is packed red blood cell transfusion. RBC transfusion improves the oxygen-carrying capacity which is achieved by enhancing the haemoglobin levels, causes dilution of HbS concentration thereby, reducing blood viscosity and boosting oxygen saturation. Furthermore, RBC transfusion is helpful in suppressing endogenous production of sickle RBCs by augmenting tissue oxygenation ( Josephson et al., 2007). There are two major types of RBC transfusion therapy: intermittent and chronic which are further classified as prophylactic or therapeutic. Intermittent transfusions are generally therapeutic in nature and administered to control acute manifestations of SCD whereas chronic transfusions are performed as general preventative measures to check complications of SCD. RBC transfusion given as a single dose is termed as simple transfusion. Exchange transfusion involves administration of a larger volume of RBCs replacing the patients RBCs that are simultaneously removed. Details of the various types of RBC transfusion and the major clinical indications for the same in SCD patients are listed in Table 1.   Ã‚  Ã‚  Ã‚  Ã‚  SCD (Source: Josephson et al., 2007) Indications for Intermittent transfusions Indications for intermittent transfusions include acute manifestations of SCD, as indicated in Table 1, that require redressal through therapeutic transfusions. However, under certain circumstances intermittent transfusions could be prophylactic such as for instance, when SCD patients are transfused before specific surgeries viz., those related to pregnancy complications or renal failure (Table 1).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Acute Chest Syndrome (ACS) describes a manifestation of SCD in which, due to sickling, infectious and noninfectious pulmonary events are complicated, resulting in a more severe clinical course. The diagnosis is the presence of a new infiltrate on chest radiography that is accompanied by acute respiratory symptoms. ACD accounts for nearly 25% of all deaths from SCD (Vichinsky, 2002). Repeated episodes of ACS are associated with an increased risk of chronic lung disease and pulmonary hypertension (Castro, 1996). The severe pulmonary events occurring in SCD may be precipitated by any trigger of hypoxia (Vichinsky, 2002). Transfusions are very efficacious and provide immediate benefit by reversing hypoxia in ACS. Transfusion of leucocyte-poor packed red cells matched for Rh, C, E, and Kell antigens can curtail antibody formation to below 1% (Vichinsky, 2002). Simple transfusions suffice for less severe cases; however, exchange transfusion is recomm ended to minimise the risk of increased viscosity. Also, chronic transfusion appears promising for prevention of recurrence in selected patients (Styles and Vichinsky, 1994). In a multicentre ACS trial, prophylactic transfusion was found to almost completely eliminate the risk of pulmonary complications (Vichinsky, 2002).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Acute Symptomatic Anaemia arises in SCD as a result of blood loss, increased RBC destruction, suppression of erythropoiesis etc. and is effectively treated with intermittent transfusion of RBCs to relieve symptoms of cardiac and respiratory distress (Josephson et al., 2007).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Aplastic Anaemia is commonly caused in SCD on account of infection of haematopoietic precursors in the bone marrow by Parvovirus B19 leading to a steep fall in RBCs. According to Josephson et al. (2007), therapeutic intermittent transfusion of RBCs is again the recommended first-line of treatment to improve total haemoglobin count and prevent cardiac decompensation. However, in those patients who are prone to fluid overload on account of cardiac or renal dysfunction an alternative transfusion strategy is to remove the whole blood and replace it with packed cells while avoiding the addition of excess volume (Josephson et al., 2007).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Acute Stroke is a high risk especially in paediatric SCD cases because of elevated cerebral flow. Enormous decline in stroke rate have occurred in children receiving intermittent simple transfusion (Adams et al., 1998). However, the identification of the stroke type would be necessary in all SCD patients in order to determine the appropriate treatment approach since the occurrence of infarctive strokes is higher in children as opposed to a higher incidence of haemorrhagic strokes in adults (Adams, 2003). Indications for Chronic Transfusions Prophylactic chronic RBC transfusion every 3 to 4 weeks to maintain HbS levels lower than 30% is crucial for preventing first as well as recurrent strokes in children (Johnson et al., 2007). The transfusions could either be chronic simple transfusion or prophylactic chronic RBC exchange transfusion. Prophylactic chronic transfusions are recommended for patients with chronic renal failure so as to avoid severe symptomatic anaemia and for those patients with SCD undergoing pregnancy with complications. However, prophylactic transfusion is not indicated for SCD patients with normal pregnancy (Tuck et al., 1987). Controversial and indeterminate indications for intermittent or chronic transfusion According to Hankins et al. (2005), chronic transfusion therapy is helpful in reducing the incidence of strokes in children but not the severity of strokes. In the case of acute priapism, improvement in patients has been observed after exchange or simple transfusion (Rifikind   et al., 1979). Yet, due to the ASPEN syndrome, transfusion currently is only a second-line therapy in the management of priapism ( Miller et al., 1995).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  RBC transfusion is a vital component in the management of symptoms and complications of SCD. It has drastically reduced the morbidity and mortality of SCD. Yet, immune-related effects such as FNHTRs and alloimmunisation to HLAs,   and nonimmune-related effects e.g., iron overload and transfusion-transmitted infections are serious adverse effects of the transfusion therapy that need to be attended to in SCD patients receiving transfusion (Johnson et al., 2007). Chronic transfusions could result in an inexorable accumulation of tissue iron that could become fatal if not treated (Cohen, 1987). Excess iron damages the liver, endocrine organs, and heart and may be fatal by adolescence (Engle, 1964). 5. Critical review of thalassemias : (i) Molecular pathogenesis The large number of inherited haemoglobin disorders known today include (a) those related to anomalies in the haemoglobin structure e.g., sickle cell disease, and (b) the thalassemias whose hallmark is globin-chain deficiency of one or other of the globin chains of adult haemoglobin in erythroid cells. ÃŽ ²-Thalassaemias These are a set of genetic disorders inherited as simple codominant traits affecting haemoglobin synthesis. Depending on the haemoglobin chain affected, 2 types of thalassemia are recognised: ÃŽ ±-thalassaemia and ÃŽ ²-thalassaemia. Homozygous ÃŽ ²-thalassaemia is marked by a quantitative deficiency of the ÃŽ ²-globin chains in the erythroid cells. A complete absence of the ÃŽ ²-globin chains occurs in homozygous ÃŽ ²o-thalassaemia whereas in homozygous ÃŽ ²+-thalassaemia the ÃŽ ²-globin chains are present at less than 30% of normal. Accounting for nearly 90% of the cases, ÃŽ ²+-thalassaemia is the most commonly observed form of ÃŽ ²-thalassaemia. The condition is termed thalassaemia major when there is microcytic hypochromic anaemia with severe haemolysis, hepatosplenomegaly, skeletal deformities and iron overload. ÃŽ ²-thalassaemia homozygotes exhibit severe transfusion-dependent anaemia in the very first year of life. Homozygotic individuals having a relatively benign clinical phe notype and surviving with or without transfusion are described as thalassaemia intermedia (Weatherall, 1969). The thalassaemias, thus, encompass a wide gamut of clinical disability from intrauterine death to a mild anaemia with no overt symptoms (Weatherall, 1997b). The coexistence of   ÃŽ ± -thalassaemia leading to reduction in the synthesis of ÃŽ ±-globin chains, and a genetic predisposition to produce high levels of HbF, could be important factors for the extensive p Causes, Symptoms and Treatments of Anaemia Causes, Symptoms and Treatments of Anaemia 1. Introduction Anaemia is a syndrome characterised by a lack of healthy red blood cells or haemoglobin deficiency in the red blood cells, resulting in inadequate oxygen supply to the tissues. The condition can be temporary, long-term or chronic, and of mild to severe intensity. There are many forms and causes of anaemia. Normal blood consists of three types of blood cells: white blood cells (leucocytes), platelets and red blood cells (erythrocytes). The first generation of erythrocyte precursors in the developing foetus are produced in the yolk sac. They are carried to the developing liver by the blood where they form mature red blood cells that are required to meet the metabolic needs of the foetus. Until the 18th week of gestation, erythrocytes are produced only by liver after which the production shifts to the spleen and the bone marrow. The life of a red blood cell is about 127 days or 4 months (Shemin and Rittenberg, 1946; Kohgo et al., 2008). The main causes of anaemia are blood loss, product ion of too few red blood cells by the bone marrow or a rapid destruction of cells.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Haemoglobin, a protein, present in the red blood cells is involved in the transport of oxygen from the lungs to all the other organs and tissues of the body. Iron is an important constituent of the haemoglobin protein structure which is intimately involved in the transport of oxygen. Anaemia is generally defined as a lower than normal haemoglobin concentration. The normal blood haemoglobin concentration is dependent on age and sex, and, according to the World Health Organisation (WHO) Expert Committee Report, anaemia results when the blood concentration of haemoglobin falls below 130 g/L in men or 120 g/L in non-pregnant women (WHO, 1968). However, the reference range of haemoglobin concentration in blood could vary depending on the ethnicity, age, sex, environmental conditions and food habits of the population analysed. According to Beutler and Warren (2006), more reasonable benchmarks for anaemia are 137 g/L for white men aged between 20 and 60 years and 132 g/L for older men. The value for women of all ages would be 122 g/L. Also, the lower limit of normal of haemoglobin concentrations of African Americans are appreciably lower than that of Caucasians (Beutler and Warren, 2006).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Besides the well recognised iron deficiency anaemia, several inherited anaemias are also known. These are mostly haemoglobinopathies. Adult haemoglobin is a tetrameric haeme-protein. Abnormalities of beta-chain or alpha-chain produce the various medically significant haemoglobinopathies. The variations in amino acid composition induced genetically impart marked differences in the oxygen carrying properties of haemoglobin. Mutations in the haemoglobin genes cause disorders that are qualitative abnormalities in the synthesis of haemoglobin (e.g., sickle cell disease) and some that are quantitative abnormalities that pertain to the rate of haemoglobin synthesis (e.g., the thalassemias) (Weatherall., 1969). In SCD, the missense mutation in the ÃŽ ²-globin gene causes the disorder. The mutation causing sickle cell anemia is a single nucleotide substitution (A to T) in the codon for amino acid 6. The substitution converts a glutamic acid codon (GAG) to a valine codon (GTG). The form of haemoglobin in persons with sickle cell anemia is referred to as HbS. Also, the valine for glutamic acid replacement causes the haemoglobin tetramers to aggregate into arrays upon deoxygenation in the tissues. This aggregation leads to deformation of the red blood cell making it relatively inflexible and restrict its movement in the capillary beds. Repeated cycles of oxygenation and deoxygenation lead to irreversible sickling and clogging of the fine capillaries. Incessant clogging of the capillary beds damages the kidneys, heart and lungs while the constant destruction of the sickled red blood cells triggers chronic anaemia and episodes of hyperbilirubinaemia.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Fanconi anaemia (FA) is an autosomal recessive condition, and the most common type of inherited bone marrow failure syndrome. The clinical features of FA are haematological with aplastic anaemia, myelodysplastic syndrome (MDS), and acute myeloid leukaemia (AML) being increasingly present in homozygotes (Tischkowitz and Hodgson, 2003). Cooleys anaemia is yet another disorder caused by a defect in haemoglobin synthesis.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Autoimmune haemolytic anaemia is a syndrome in which individuals produce antibodies directed against one of their own erythrocyte membrane antigens. The condition results in diminished haemoglobin concentrations on account of shortened red blood cell lifespan (Sokol et al., 1992).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Megaloblastic anaemia is a blood disorder in which anaemia occurs with erythrocytes which are larger in size than normal. The disorder is usually associated with a deficiency of vitamin B12 or folic acid . It can also be caused by alcohol abuse, drugs that impact DNA such as anti-cancer drugs, leukaemia, and certain inherited disorders among others (Dugdale, 2008).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Malaria causes increased deformability of vivax-infected red blood cells (Anstey et al., 2009). Malarial anaemia occurs due to lysis of parasite-infected and non-parasitised erythroblasts as also by the effect of parasite products on erythropoiesis (Ru et al., 2009).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Large amounts of iron are needed for haemoglobin synthesis by erythroblasts in the bone marrow. Transferrin receptor 1 (TfR1) expressed highly in erythroblasts plays an important role in extracellular iron uptake (Kohgo et al., 2008). Inside the erythroblasts, iron transported into the mitochondria gets incorporated into the haeme ring in a multistep pathway. Genetic abnormalities in this pathway cause the phenotype of ringed sideroblastic anemias (Fleming, 2002). The sideroblastic anemias are a heterogeneous group of acquired and inherited bone marrow disorders, characterised by mitochondrial iron overload in developing red blood cells. These conditions are diagnosed by the presence of pathologic iron deposits in erythroblast mitochondria (Bottomley, 2006).    2. Classification of anaemia Anaemia can be generally classified based on the morphology of the red blood cells, the pathogenic spectra or clinical presentation (Chulilla et al., 2009). The morphological classification is based on mean corpuscular volume (MCV) and comprises of microcytic, macrocytic and normocytic anaemia.   Ã‚  Ã‚  Ã‚  Ã‚  (a) Microcytic anaemia refers to the presence of RBCs smaller than normal volume, the reduced MCV ( 15 would probably indicate IDA (Chulilla et al., 2009).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  In macrocytic anaemia, erythrocytes are larger (MCV > 98 fL) than their normal volume (MCV = 82-98 fL). Vitamin B12 deficiency leads to delayed DNA synthesis in rapidly growing hematopoietic cells, and can result in macrocytic anemia. Drugs that interfere with nucleic acid metabolism, such as.hydroxyurea increases MCV (> 110 fL) while alcohol induces a moderate macrocytosis (100-110 fL). In the initial stage, most anaemias are normocytic. The causes of normocytic anaemia are nutritional deficiency, renal failure and haemolytic anemia (Tefferi, 2003). The most common normocytic anaemia in adults is anaemia of chronic disease (ACD) (Krantz, 1994). Common childhood normocytic anaemias are, besides iron deficiency anaemia, those due to acute bleeding, sickle cell anemia, red blood cell membrane disorders and current or recent infections especially in the very young (Bessman et al., 1983). Homozygous sickle cell disease is the most common cause of h aemolytic normocytic anemias in children (Weatherall DJ, 1997a).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  In practice, the morphological classification is quicker and therefore, more useful as a diagnostic tool. Besides, MCV is also closely linked to mean corpuscular haemoglobin (MCH), which denotes mean haemoglobin per erythrocyte expressed in picograms (Chulilla et al., 2009). Thus, MCV and MCH decrease simultaneously in microcytic, hypochromic anemia and increase together in macrocytic, hyperchromic anemia.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Pathogenic classification of anaemia is based on the production pattern of RBC: whether anaemia is due to inadequate production or loss of erythrocytes caused by bleeding or haemolysis. This approach is useful in those cases where MCV is normal. Pathogenic classification is also essential for proper recognition of the mechanisms involved in the genesis of anaemia. Based on the pathogenic mechanisms, anaemia is further divided into two types namely, (i) hypo-regenerative in which the bone marrow production of erythrocytes is decreased because of impaired function, decreased number of precursor cells, reduced bone marrow infiltration, or lack of nutrients; and (ii) regenerative: when bone marrow upregulates the production of erythrocytes in response to the low erythrocyte mass (Chulilla et al., 2009). This is typified by increased generation of erythropoietin in response to lowered haemoglobin concentration, and also reflects a loss of erythrocyt es, due to bleeding or haemolysis. The reticulocyte count is typically higher.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Sickle cell disease is characterised by sickled red cells.   The first report of SCD was published a century ago noting the presence of peculiar elongated cells in blood by James Herrick, an American physician (1910). Pauling et al. (1949) described it as a molecular disease. The molecular nature of sickle haemoglobin (Hb S) in which valine is substituted for glutamic acid at the sixth amino acid position in the beta globin gene reduces the solubility of Hb, causing red cells to sickle (Fig. 1). Sickling of cells occurs at first reversibly, then finally as a state of permanent distortion, when cells containing HbS and inadequate amounts of other haemoglobins including foetal haemoglobin, which retards sickling, become deoxygenated (Bunn, 1997). The abnormal red cells break down, leading to anaemia, and clog blood vessels with aggregates, leading to recurrent episodes of severe pain and multiorgan ischaemic damage (Creary et al., 2007). The high levels of inflammatory cytokines in SCD may promote retention of iron by macrophage/reticuloendothelial cells and/or renal cells. SCD care commonly depends on transfusion that results in iron overload (Walter et al., 2009). 3. Pathogenesis of anaemia Anaemia is a symptom , or a syndrome, and not a disease (Chulilla et al., 2009). Several types of anaemia have been recognised, the pathogenesis of each being unique. Iron deficiency anaemia (IDA) is the most common type of anaemia due to nutritional causes encountered worldwide (Killip et al., 2008). Iron is one of the essential micronutrients required for normal erythropoietic function While the causes of iron deficiency vary significantly depending on chronological age and gender, IDA can reduce work capacity in adults (Haas Brownlie, 2001) and affect motor and mental development in children (Halterman et al., 2001). The metabolism of iron is uniquely controlled by absorption rather than excretion (Siah et al., 2006). Iron absorption typically occurring in the duodenum accounts for only 5 to 10 per cent of the amount ingested in homoeostatis. The value decreases further under conditions of iron overload, and increases up to fivefold under conditions of iron depletion (Killip et al., 2008). Iron is ingested as haem iron (10%) present in meat, and as non-haem ionic form iron (90%) found in plant and dairy products. In the absence of a regulated excretion of iron through the liver or kidneys, the only way iron is lost from the body is through bleeding and sloughing of cells. Thus, men and non-menstruating women lose about 1 mg of iron per day while menstruating women could normally lose up to 1.025 mg of iron per day (Killip et al., 2008). The requirements for erythropoiesis   which are typically 20-30 mg/day   are dependent on the internal turnover of iron (Munoz et al., 2009) For example, the amount of iron required for daily production of 300 billion RBCs (20-30 mg) is provided mostly by recycling iron by macrophages (Andrews, 1999).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Iron deficiency occurs when the metabolic demand for iron exceeds the amount available for absorption through consumption. Deficiency of nutritional intake of iron is important, while abnormal iron absorption due to hereditary or acquired iron-refractory iron deficiency anemia (IRIDA) is another important cause of unexplained iron deficiency. However, IDA is commonly attributed to blood loss e.g., physiological losses in women of reproductive age. It might also represent occult bleeding from the gastrointestinal (GI) tract generally indicative of malignancy (Hershko and Skikne, 2009).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Iron absorption and loss play an important role in the pathogenesis and management of IDA. Human iron disorders are necessarily disorders of iron balance or iron distribution. Iron homeostasis involves accurate control of intestinal iron absorption, efficient utilisation of iron for erythropoiesis, proper recycling of iron from senescent erythrocytes, and regulated storage of iron by hepatocytes and macrophages (Andrews, 2008). Iron deficiency is largely acquired, resulting from blood loss (e.g., from intestinal parasitosis), from inadequate dietary iron intake, or both. Infections, for example, with H pylori, can lead to profound iron deficiency anemia without significant bleeding. Genetic defects can cause iron deficiency anaemia. Mutations in the genes encoding DMT1 (SLC11A2) and glutaredoxin 5 (GLRX5) lead to autosomal recessive hypochromic, microcytic anaemia (Mims et al., 2005). Transferrin is a protein that keeps iron nonreactive in the circulation, and delivers iron to cells possessing specific transferrin receptors such as TFR1 which is found in largest amounts on erythroid precursors. Mutations in the TF gene leading to deficiency of serum transferrin causes disruption in the transfer of iron to erythroid precursors thereby producing an enormous increase in intestinal iron absorption and consequent tissue iron deposition (Beutler et al., 2000). Quigley et al. (2004) found a haem exporter, FLVCR, which appears to be necessary for normal erythroid development. Inactivation of FLVCR gene after birth in mice led to severe macrocytic anaemia, indicating haem export to be important for normal erythropoiesis.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  The anaemia of chronic disease (ACD) found in patients with chronic infectious, inflammatory, and neoplastic disorders is the second most frequently encountered anaemia after iron-deficiency anaemia. It is most often a normochromic, normocytic anaemia that is primarily caused by an inadequate production of red cells, with low reticulocyte production (Krantz, 1994). The pathogenesis of ACD is unequivocally linked to increased production of the cytokines including tumour necrosis factor, interleukin-1, and the interferons that mediate the immune or inflammatory response. The various processes leading to the development of ACD such as reduced life span of red cells, diminished erythropoietin effect on anaemia, insufficient erythroid colony formation in response to erythropoietin, and impaired bioavailability of reticuloendothelial iron stores appear to be caused by inflammatory cytokines (Means, 1996;2003). Although iron metabolism is characterist ically impaired in ACD, it may not play a key role in the pathogenesis of ACD (Spivak, 2002). Neither is the lack of available iron central to the pathogenesis of the syndrome, according to Spivak (2002), who found reduced iron absorption and decreased erythroblast transferrin-receptor expression to be the result of impaired erythropoietin production and inhibition of its activity by cytokines. However, reduced erythropoietin activity, mostly from reduced production, plays a pivotal role in the pathogenesis of ACD observed in systemic autoimmune diseases (Bertero and Caligaris-Cappio, 1997). Indeed, iron metabolism as well as nitric oxide (NO), which contributes to the regulation of iron cellular metabolism are involved in the pathogenesis of ACD in systemic autoimmune disorders. Inflammatory mediators, particularly the cytokines, are important factors involved in the pathogenesis of the anaemia of chronic disease, as seen in rheumatoid arthritis anaemia (Baer et al., 1990), the cyt okines causing impairment of erythroid progenitor growth and haemoglobin production in developing erythrocytes.     Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Anaemia is also commonly found in cases of congestive heart failure (CHF), again caused by excessive cytokine production leading to reduced erythropoietin secretion, interference with erythropoietin activity in the bone marrow and reduced iron supply to the bone marrow (Silverberg et al., 2004). However, in the presence of chronic kidney insufficiency, abnormal erythropoietin production in the kidney plays a role in the pathogenesis of anaemia in CHF.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  The myelodysplastic syndromes (MDS) are common haematological malignancies affecting mostly the elderly as age-related telomere shortening enhances genomic instability (Rosenfeld and List, 2000). Radiation, smoking and exposure to toxic compounds e.g., pesticides, organic chemicals and heavy metals, are factors promoting the onset of MDS via damage caused to progenitor cells, and, thereby, inducing immune suppression of progenitor cell growth and maturation. TNF- and other pro-apoptotic cytokines could play a central role in the impaired haematopoiesis of MDS (Rosenfeld and List, 2000). Premature intramedullary cell death brought about by excessive apoptosis is another important pathogenetic mechanism in MDS (Aul et al., 1998).     Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Sickle cell disease (SCD) arising from a point mutation in the ÃŽ ²-globin gene and leading to the expression of haemoglobin S (HbS) is the most common monogenetic disorder worldwide. Chronic intravascular haemolysis and anaemia are some important characteristics of SCD. Intravascular haemolysis causes endothelial dysfunction marked by reduced nitric oxide (NO) bioavailability and NO resistance, leading to acute vasoconstriction and, subsequently, pulmonary hypertension (Gladwin and Kato, 2005).    However, a feature that differentiates SCD from other chronic haemolytic syndromes is the persistent and intense inflammatory condition present in SCD. The primary pathogenetic event in SCD is the intracellular polymerisation or gelation of deoxygenated HbS leading to rigidity in erythrocytes (Wun, 2001). The deformation of erythrocytes containing HbS is dependent on the concentration of haemoglobin in the deoxy conformation (Rodgers et al., 1985). It has been demonstrated that sickle monocytes are activated which, in turn, activate endothelial cells and cause vascular inflammation. The vaso-occlusive processes in SCD involve inflammatory and adhesion molecules such as the cell adhesion molecules (CAM family), which play a role in the firm adhesion of reticulocytes and leukocytes to endothelial cells, and the selectins, which play a role in leukocyte and platelet rolling on the vascular wall (Connes et al., 2008). Thus, inflammation, leucocyte adhesion to vascular endothelium, and subsequent endothelial injury are other crucial factors contributing to the pathogenesis of SCD (Jison et al., 2004). 4. Current therapies for clinical management of sickle cell diseaseincludingacritical appraisal of transfusion Between 1973 and 2003, the average life expectancy of a patient with SCD increased dramatically from a mere 14 years to 50 years thanks to the development of comprehensive care models and painstaking research efforts in both basic sciences especially molecular and genetic studies, and clinical aspects of SCD (Claster and Vichinsky, 2003). The clinical manifestations of SCD are highly variable. Both the phenotypic expression and intensity of the syndrome are vastly different among patients and also vary longitudinally within the same patient (Ballas, 1998). New pathophysiological insights available have enabled treatments to be developed for the recognised haematologic and nonhaematologic abnormalities in SCD (Claster and Vichinsky, 2003). The main goals of SCD treatment are symptom alleviation, crises avoidance and effective management of disease complications. The strategy adopted is primarily palliative in nature, and consists of supportive, symptomatic and preventative approaches to therapy. Symptomatic management includes pain mitigation, management of vasoocclusive crisis, improving chronic haemolytic anaemia, treatment of organ failure associated with the disease, and detection and treatment of pulmonary hypertension (Distenfeld and Woermann, 2009). The preventative strategies include use of prophylactic antibiotics (e.g., penicillin) in children, prophylactic blood transfusion for prevention of stroke in patients especially young children who are at a very high risk of stroke, and treatment with hydroxyurea of patients experiencing frequent acute painful episodes (Ballas, 2002). Currently, curative therapy for sickle cell anaemia is only available through bone marrow and stem cell transplantation. Hematopoietic cell transplantation using stem cells from a matched sibling donor has yielded excellent results in paediatric patients (Krishnamurti, 2007). Curative gene therapy is still at the exploratory stage (Ballas, 2002). Current and potential therapies The potential treatment strategies basically target cellular dehydration, sickle haemoglobin concentrations, endothelial dysfunction, and abnormal coagulation regulation (Claster and Vichinsky, 2003). HbS concentrations are essentially tackled through transfusions while approaches to reduce HbS polymerisation which is the main mechanism for the development of vaso-occlusion include (a) increasing foetal haemoglobin (HbF) concentration using hydroxyurea (Fig. 2), butyrate, or erythropoietin, and (b) preventing sickle cell dehydration using Clotrimazole (Fig. 3) or Mg2+pidolate. Hydroxyurea therapy increases the production of HbF in patients with sickle cell anaemia, and, thereby, inhibits the polymerisation of HbS and alleviates both the haemolytic and vaso-occlusive manifestations of the disease (Goldberg et al., 1990). Recombinant erythropoietin also increases the number of reticulocytes with HbF. Additionally, it has been observed that administration of intravenous recombinant eryt hropoietin with iron supplementation alternating with hydroxyurea enhances HbF levels more than hydroxyurea alone (Rodgers et al., 1993). As SCD is essentially characterized by an abnormal state of endothelial cell activation   that is, a state of inflammation, a pharmacologic approach to inhibit endothelial cell activation has proved clinically beneficial (Hebbel and Vercellotti, 1997). Thus, administration of sulfasalazine which is a powerful inhibitor of activation of nuclear factor (NF)-B, the transcription factor promoting expression of genes for a number of pro-adhesive and procoagulant molecules on endothelium to humans has been found to provide transcriptional regulation of SCD at the endothelium level (Solovey et al., 2001). Red blood cell transfusion : a critical appraisal A key therapy that is applied regularly in the clinical management of patients with SCD is packed red blood cell transfusion. RBC transfusion improves the oxygen-carrying capacity which is achieved by enhancing the haemoglobin levels, causes dilution of HbS concentration thereby, reducing blood viscosity and boosting oxygen saturation. Furthermore, RBC transfusion is helpful in suppressing endogenous production of sickle RBCs by augmenting tissue oxygenation ( Josephson et al., 2007). There are two major types of RBC transfusion therapy: intermittent and chronic which are further classified as prophylactic or therapeutic. Intermittent transfusions are generally therapeutic in nature and administered to control acute manifestations of SCD whereas chronic transfusions are performed as general preventative measures to check complications of SCD. RBC transfusion given as a single dose is termed as simple transfusion. Exchange transfusion involves administration of a larger volume of RBCs replacing the patients RBCs that are simultaneously removed. Details of the various types of RBC transfusion and the major clinical indications for the same in SCD patients are listed in Table 1.   Ã‚  Ã‚  Ã‚  Ã‚  SCD (Source: Josephson et al., 2007) Indications for Intermittent transfusions Indications for intermittent transfusions include acute manifestations of SCD, as indicated in Table 1, that require redressal through therapeutic transfusions. However, under certain circumstances intermittent transfusions could be prophylactic such as for instance, when SCD patients are transfused before specific surgeries viz., those related to pregnancy complications or renal failure (Table 1).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Acute Chest Syndrome (ACS) describes a manifestation of SCD in which, due to sickling, infectious and noninfectious pulmonary events are complicated, resulting in a more severe clinical course. The diagnosis is the presence of a new infiltrate on chest radiography that is accompanied by acute respiratory symptoms. ACD accounts for nearly 25% of all deaths from SCD (Vichinsky, 2002). Repeated episodes of ACS are associated with an increased risk of chronic lung disease and pulmonary hypertension (Castro, 1996). The severe pulmonary events occurring in SCD may be precipitated by any trigger of hypoxia (Vichinsky, 2002). Transfusions are very efficacious and provide immediate benefit by reversing hypoxia in ACS. Transfusion of leucocyte-poor packed red cells matched for Rh, C, E, and Kell antigens can curtail antibody formation to below 1% (Vichinsky, 2002). Simple transfusions suffice for less severe cases; however, exchange transfusion is recomm ended to minimise the risk of increased viscosity. Also, chronic transfusion appears promising for prevention of recurrence in selected patients (Styles and Vichinsky, 1994). In a multicentre ACS trial, prophylactic transfusion was found to almost completely eliminate the risk of pulmonary complications (Vichinsky, 2002).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Acute Symptomatic Anaemia arises in SCD as a result of blood loss, increased RBC destruction, suppression of erythropoiesis etc. and is effectively treated with intermittent transfusion of RBCs to relieve symptoms of cardiac and respiratory distress (Josephson et al., 2007).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Aplastic Anaemia is commonly caused in SCD on account of infection of haematopoietic precursors in the bone marrow by Parvovirus B19 leading to a steep fall in RBCs. According to Josephson et al. (2007), therapeutic intermittent transfusion of RBCs is again the recommended first-line of treatment to improve total haemoglobin count and prevent cardiac decompensation. However, in those patients who are prone to fluid overload on account of cardiac or renal dysfunction an alternative transfusion strategy is to remove the whole blood and replace it with packed cells while avoiding the addition of excess volume (Josephson et al., 2007).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Acute Stroke is a high risk especially in paediatric SCD cases because of elevated cerebral flow. Enormous decline in stroke rate have occurred in children receiving intermittent simple transfusion (Adams et al., 1998). However, the identification of the stroke type would be necessary in all SCD patients in order to determine the appropriate treatment approach since the occurrence of infarctive strokes is higher in children as opposed to a higher incidence of haemorrhagic strokes in adults (Adams, 2003). Indications for Chronic Transfusions Prophylactic chronic RBC transfusion every 3 to 4 weeks to maintain HbS levels lower than 30% is crucial for preventing first as well as recurrent strokes in children (Johnson et al., 2007). The transfusions could either be chronic simple transfusion or prophylactic chronic RBC exchange transfusion. Prophylactic chronic transfusions are recommended for patients with chronic renal failure so as to avoid severe symptomatic anaemia and for those patients with SCD undergoing pregnancy with complications. However, prophylactic transfusion is not indicated for SCD patients with normal pregnancy (Tuck et al., 1987). Controversial and indeterminate indications for intermittent or chronic transfusion According to Hankins et al. (2005), chronic transfusion therapy is helpful in reducing the incidence of strokes in children but not the severity of strokes. In the case of acute priapism, improvement in patients has been observed after exchange or simple transfusion (Rifikind   et al., 1979). Yet, due to the ASPEN syndrome, transfusion currently is only a second-line therapy in the management of priapism ( Miller et al., 1995).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  RBC transfusion is a vital component in the management of symptoms and complications of SCD. It has drastically reduced the morbidity and mortality of SCD. Yet, immune-related effects such as FNHTRs and alloimmunisation to HLAs,   and nonimmune-related effects e.g., iron overload and transfusion-transmitted infections are serious adverse effects of the transfusion therapy that need to be attended to in SCD patients receiving transfusion (Johnson et al., 2007). Chronic transfusions could result in an inexorable accumulation of tissue iron that could become fatal if not treated (Cohen, 1987). Excess iron damages the liver, endocrine organs, and heart and may be fatal by adolescence (Engle, 1964). 5. Critical review of thalassemias : (i) Molecular pathogenesis The large number of inherited haemoglobin disorders known today include (a) those related to anomalies in the haemoglobin structure e.g., sickle cell disease, and (b) the thalassemias whose hallmark is globin-chain deficiency of one or other of the globin chains of adult haemoglobin in erythroid cells. ÃŽ ²-Thalassaemias These are a set of genetic disorders inherited as simple codominant traits affecting haemoglobin synthesis. Depending on the haemoglobin chain affected, 2 types of thalassemia are recognised: ÃŽ ±-thalassaemia and ÃŽ ²-thalassaemia. Homozygous ÃŽ ²-thalassaemia is marked by a quantitative deficiency of the ÃŽ ²-globin chains in the erythroid cells. A complete absence of the ÃŽ ²-globin chains occurs in homozygous ÃŽ ²o-thalassaemia whereas in homozygous ÃŽ ²+-thalassaemia the ÃŽ ²-globin chains are present at less than 30% of normal. Accounting for nearly 90% of the cases, ÃŽ ²+-thalassaemia is the most commonly observed form of ÃŽ ²-thalassaemia. The condition is termed thalassaemia major when there is microcytic hypochromic anaemia with severe haemolysis, hepatosplenomegaly, skeletal deformities and iron overload. ÃŽ ²-thalassaemia homozygotes exhibit severe transfusion-dependent anaemia in the very first year of life. Homozygotic individuals having a relatively benign clinical phe notype and surviving with or without transfusion are described as thalassaemia intermedia (Weatherall, 1969). The thalassaemias, thus, encompass a wide gamut of clinical disability from intrauterine death to a mild anaemia with no overt symptoms (Weatherall, 1997b). The coexistence of   ÃŽ ± -thalassaemia leading to reduction in the synthesis of ÃŽ ±-globin chains, and a genetic predisposition to produce high levels of HbF, could be important factors for the extensive p