Effects of Slavery on America

Effects of Slavery on American History Andrew Avila US History 1301 Dr. Raley April 18, 2013 The U. S. Constitution is primarily based on compromise between larger and smaller states, and more importantly, between northern and southern states. One major issue of the northern and southern states throughout American history is the topic of slavery. Although agreements such as the Three-Fifths Compromise in 1787, and the Thirteenth Amendment in 1865 were adapted to reduce and outlaw slavery, it took many years for slavery to be completely abolished and allow blacks the freedom they had been longing for.The Three-Fifths Compromise was a agreement reached at the Constitutional Convention of 1787 in Philadelphia in which three-fifths of states’ slaves would be counted as representation regarding distribution of taxes and apportionment of members to the House of Representatives[1]. This meant that slave owners would be taxed on the number of slaves they owned as well as states receiv ing representation for the allotted 3/5, or â€Å"Federal ratio,† of slaves owned.During the Continental Congress of 1783, a committee was appointed to decide upon a method to be integrated in the Articles of Confederation to prevent states from ignoring their fair share of the tax burden. The proposed fix was to tax based on population rather than property value. Delegates who opposed slavery only wanted to count all free inhabitants of each state, while supporters of slavery wanted to count all slaves for representation purposes only and not for taxation.Being that southern states were heavily populated with slaves, naturally, northern states feared that the south would gain a political upper-hand and become extremely powerful[2]. Seeing such opposition from northern and southern states, representatives James Wilson and Roger Sherman came up with a plan that stemmed from the one proposed at the Continental Congress. The Three-Fifths Compromise, which was designed to meet th e demands of both sides, gave the south their much anticipated representation, while easing the fears of the north of being politically overpowered by the south[3].After the Virginia Plan was rejected, the Three-Fifths Compromise seemed to guarantee more political power to the south. As a result, southern states dominated the Presidency and Speakership of the House. While the south gained more representation because of the higher ownership of slaves, the north gained very little. However, the longterm results of the Three-Fifths Compromise did not work well to the southern states’ advantage[4]. The increased importation of slaves to the south upset the north leading to the Missouri Compromise.The Missouri Compromise prohibited slavery in the former Louisiana Territory north of the 36o 30’. By 1820, the northern states began to grow faster than southern states resulting in the fall from southern representation in the House of Representatives. The Three-Fifths Compromise paved the way for the Thirteenth Amendment in 1865 which outlaws slavery. However, the Thirteenth Amendment was meant to guarantee slavery. In 1863, Abraham Lincoln issued an Emancipation Proclamation declaring that any people held as slaves would be free[5].Many people questioned the validity of the Proclamation as well as President Lincoln’s power. Because President Lincoln failed to mention that slaves in the loyalist states would be free in the Proclamation, many doubted the effect would last beyond restoration of the states[6]. Although the Emancipation Proclamation declared that slaves would be free, it did not actually free any slaves in border states nor did it abolish slavery. President Lincoln and other supporters decided it was necessary to include an amendment to the Constitution abolishing slavery.The Thirteenth Amendment was the first amendment proposed in 60 years. The Thirteenth Amendment was the only slavery-related bill to oppose and abolish slavery while o ther bills protected slavery[7]. Eventually, the bill was taken to the Senate and passed on April 8, 1864. Although the bill was passed as an effort to keep the country united, it was stopped from being ratified as the south began to secede and the Union dissolved. This prevented the bill from becoming an actual law. President Lincoln took active measures to get the proposed bill on the Republican Party platform for the 1864 presidential election.After several months of debate, the bill finally reached the two-thirds vote on January 31, 1865, although the signed amendment’s archival copy states the bill was passed February 1, 1865[8]. After the approval of the Thirteenth Amendment, Congress passed four statutes known as the Reconstruction Acts. The Reconstruction Congress was required to pass two laws that implemented the Thirteenth Amendment[9]. The first was the Civil Rights Act declaring that freed slaves were allowed to enjoy the same rights as white people. This law made it a crime on the federal level to deprived freed slaves of these rights.The second was the Anti-Peonage Act of 1867 which made the holding of any person as a slave unlawful[10]. The Thirteenth Amendment completed the abolition of slavery in the United States. The process to abolish slavery began with President Lincoln’s issuing of the Emancipation Proclamation in 1863. Although the Thirteenth Amendment outlaws slavery and involuntary servitude, officials had to selectively enforce laws such as vagrancy forcing blacks to be subject to involuntary servitude. The southern states' attitudes towards abolition made it nearly impossible for blacks to shake being ex-slaves.After the abolition of slavery, life for Black Americans got even more difficult before it could get better. Public beatings and lynchings became and everyday occurrence through â€Å"white supremacy groups† such as the Ku Klux Klan. Segregation between whites and blacks had become widespread at the time a s well. Many blacks found it difficult to survive off the poor wages they received and terrible living situations. Slavery was not legal or illegal until each individual state made it so. Up until that point, slavery was an accepted common law practice.However, after slavery was declared illegal in individual states and had been outlawed, many slave owners, and slaves alike, needed to adjust to the newly acquired changes. Needless to say, this was a change that would take many years to adapt to. To this day, these movements are still discussed as the judicial system . Many people still do not support the abolition of slavery. The United States Constitution states that slavery and involuntary servitude are illegal unless ordered by the court. However, this does not mean that any individual may own a slave.This simply means that if a person is convicted of a crime, said person may be ordered to prison or community service. This however does not mean that there are absolutely no cases of slavery in America today. Although in slightly different form, slavery still exists today despite the trial and error endured by the American government to abolish slavery in its entirety. Slavery today is known as human trafficking. Not only does human trafficking include involuntary servitude and forced labor, but various other acts that are to be carried out by those who are being held as slaves.Human trafficking is one of the biggest crimes committed today. Throughout history many measures have been taken to prohibit and outlaw slavery. However, documents such as the Three-Fifths Compromise and the Thirteenth Amendment were two of the major stepping stones in the direction of abolishing slavery. The issue of slavery has been around since the beginning of the United States and has undergone many changes over time. With agreements such as the Three-Fifths Compromise and the Thirteenth Amendment, slavery was able to be decreased and eventually abolished.Bibliography Peter Robins on. Uncommon Knowledge: A Slave to the System? Thomas Jefferson and Slavery. Hoover Institution, 2009. Garry Wills. â€Å"Negro President†: Jefferson and the Slave Power. Houghton Mifflin Company. New York, 2003. Herman Belz. Emancipation and Equal Rights: Politics and Constitutionalism in the Civil War Era. New York, 1978. Michael Vorenberg. Final Freedom: The Civil War, the Abolition of Slavery, and the Thirteenth Amendment. Cambridge University Press, 2001. Report of the Brown University Steering Committee on Slavery and Justice.The House Joint Resolution proposing the 13th amendment to the Constitution, January 31, 1865; Enrolled Acts and Resolutions of Congress, 1789-1999; General Records of the United States Government; Record Group 11; National Archives Harp Weekly. Ratification and Results. 2008. Oman Nathan. Specific Performance and the Thirteenth Amendment. Minnesota Law Review, Forthcoming. 2008. Unknown Author. â€Å"The Slavery Compromises†. University of Louisiana-Lafayette Computing Support Services. Unknown Date. Gilder Lehrman Institute. The Three-Fifths Compromise. Digital History. 2013. ———————- [1] Gilder Lehrman Institute. The Three-Fifths Compromise. Digital History. 2013. [2] Peter Robinson. Uncommon Knowledge: A Slave to the System? Thomas Jefferson and Slavery. Hoover Institution, 2009. [3] Unknown Author. â€Å"The Slavery Compromises†. University of Louisiana-Lafayette Computing Support Services. Unknown Date [4] Peter Robinson. Uncommon Knowledge: A Slave to the System? Thomas Jefferson and Slavery. Hoover Institution, 2009. [5] Herman Belz. Emancipation and Equal Rights: Politics and Constitutionalism in the Civil War Era. New York, 1978. 6] Michael Vorenberg. Final Freedom: The Civil War, the Abolition of Slavery, and the Thirteenth Amendment. Cambridge University Press, 2001. [7] 3Herman Belz. Emancipation and Equal Rights: Politics and Constitutionalism in the Civil War Era. New York, 1978. [8] 3Herman Belz. Emancipation and Equal Rights: Politics and Constitutionalism in the Civil War Era. New York, 1978. [9] Oman Nathan. Specific Performance and the Thirteenth Amendment. Minnesota Law Review, Forthcoming. 2008. [10] Oman Nathan. Specific Performance and the Thirteenth Amendment. Minnesota Law Review, Forthcoming. 2008.

Imperfections of modern society Essay

Fashion may be described as the predominant style at any given time due to ones mode of expression or presentation. Ones personality may be defined by the clothes they have selected to wear. Celebrities and fashion ads seem to demonstrate that it is acceptable to wear extremely revealing clothes and promote their outfits. Sexually provocative people with strong personalities may choose to wear clothes with inappropriate innuendos or phrases written on them. Modern fashion illustrates the social acceptance of provocative clothing, which reflects upon our cultures bold behavior. see more:why fashion is important It is thought that the clothes society chooses to wear defines ones intentions, character and gives others a basis on how to interpret personality. People have bold behaviours because of what they wear. Many are too open with what they wear making it seem as if modern fashion is mainly about sex appeal. Modern culture is mainly concerned with how others will interpret them and their appearance. Therefore society uses this to make oneself more appealing. If someone were to dress in revealing clothing, others will construe this as they are trying make themselves as sexually appealing as possible. However if someone were to dress in less revealing clothes they would not be in to the hype of sex appeal. This shows how modern culture reflects on the clothes being worn. These people who are only worried about revealing themselves through outfits clearly have bold behaviours because they care what society thinks of them. People tend to act more outgoing when they are dress in clothes that they are comfortable wearing. No matter what type of clothing a person wears it can be an influence that alters others perception of the character of a person. Revealing clothing that is exposed by media can be dangerous to people’s thoughts on modern fashion. Celebrities feel that it acceptable to wear whatever they please. Miley Cyrus is an excellent example of this. She has recently had a tendency of wearing inappropriate clothing on stage and in her music videos. Her personality reflects how she dresses by showing how much she does not care about what people think of her. Miley is very revealing in her videos and her lyrics show her personality of being so careless of what other people think. â€Å"Its our party we can do what we want to†¦ Its my mouth I can say what I want to†(Cyrus). In her lyrics, she is inferring that she is above the law. This is the unstated conclusion throughout her song. She shows her careless attitude in her lyrics but also in her music videos. Miley is a role model to many but she rolls around on the floor wearing nothing but underwear and a tank top making it seem like this is acceptable as she has a young, naive audience that does not know between right and wrong. She also does dance moves that are so inappropriate that young children should not watch this. Miley used to dress normally and she was an idol for many young girls growing up starring as Hannah Montana. Now she has changed personality by exemplifying it through her fashion. Clothing with sexual or inappropriate phrases written on them has become more popular in modern culture because of the popular idols. People with forward personalities tend to buy clothes that reflect on the way that one would want to be judged. Select societies with careless attitudes wear clothing that can be offensive to other people. Shirts with phrases such as â€Å"Orgasm Donor† and â€Å"Drink Up Bitches† are some of many examples of the offensiveness that people display through their clothing. People who wear clothing like this are often sexually provocative people who try to resemble the looks of their idols. Society feels the need encourage to others that it is socially acceptable to look sexually appealing. In reality this type of clothing is obnoxious and reflects poorly on modern culture by giving it a bad label. The popularity of wearing offensive clothing has increased due to people trying to â€Å"fit in†. People who are unsure of what type of personality they have are often the ones who go with the latest and most popular fashion. Our cultures outgoing behaviour is based on the social acceptance that modern fashion portrays. It is believed that the clothes that a person may wear can reflect on their personality. Celebrities who wear excessively revealing clothing tend to set an image that modern culture wants to follow. Miley Cyrus is one of the many celebrities who contribute to this. People who have audacious personalities are usually ones to try to keep up with modern fashion. These people have clothing with sexually provocative expressions written on them. Fashion can be defined as the prevailing style or etiquette. Society may dress to support feelings, actions or how others should interpret their character. Works Cited Cyrus, Miley. â€Å"MILEY CYRUS – WE CAN’T STOP LYRICS. † Directlyrics. N. p. , n. d. Web. 26 Sept. 2013.

The Language of Reality Essay Example | Topics and Well Written Essays - 8000 words

The Language of Reality - Essay Example Beyond elementary semantic structures numerous sub-layers of meaning and communication exist to both enrich and complicate the way in which we interact and express our ideas and emotions. It is not what we say, but how we say it. The world of artificial intelligence and its struggle to embrace the complexities of everyday communication shows just how interdependent language, external cultural foces and the personal realm of experience can be. A simple de-coding or patterning of linguistic structures as we understand them is barely enough to compose the bare bones of the seemingly simple ways in which we communicate. The gap between intention and reception can create a crossfire of miscommunication - where meaning becomes alienated from form and the most intangible aspects of speech are cast into the spotlight. In the theoretical space between intention and reception - where communication can either prosper or become fragmented - lie determinants such as perception and recognition. We therefore largely depend upon these two elements to formulate successful interactions, and to form the fabric of what we perceive as reality - in the sense that we depend upon information to guide, instruct, elucidate and define the world around us. Sayre (1965, p. 177), examines the distinction between perception and recognition - and the roles they play in our understanding and interpretation of the world around us: "According to the theory outlined in Plato "Meno" and Phaedo, acquisition of knowledge is a matter of recollection or recognition. As someone comes to know that about which he has been ignorant, he "cognizes again" .... If I have never seen, been told about, read about or in some other way come to know about gooseberries, then upon seeing a gooseberry for the first time I scarcely could be said to recognize it. The next time I see a gooseberry I probably will recognize it, if not by name then at least as an object of the sort I had seen some time previously. But if the first time one perceives an object is the first time one has ever been cognitively aware of such an object, perforce at that time one does not recognize it. It is commonplace, on the other hand, that we perceive objects which we have never perceived before, nor learned about in any other way." In this understanding of recognition and perception, the act of recognition is, by definition, rooted in the realm of memory and past experience. Memory, it is generally accepted, tends towards subjectivity, embellishment and is often powerfully influenced by the emotions or mindset that were in force at the time when the incident occured. It follows that recognition is unreliable as an objective conduit for accurately conveying intended meaning - as it will always be influenced by a recipient's internalised framework of understanding. In this way, the eventual meaning conveyed by a piece of information is outside of the control of the speaker or communicator from the moment the idea leaves their immediate sphere and enters a communication channel - whether that channel be through the medium of speech, or through a technological pathway such as the internet. Once a piece of information is liberated from the person in possession of its intended meaning - it immediately falls prey to the co-authorship of social context and recipient subjectivity. Caught in a fragmented point of juncture between initial source, external influences and final perception and recognition - a message is defined and understood by a melange of often contradictory 'realities'1 which - by way of their very merger and interconnectedness -

Bench mark assignment Essay Example | Topics and Well Written Essays - 1250 words

Bench mark assignment - Essay Example However, the bacteria spreads faster and affects the internal systems such as the lungs. The major symptoms of the disease include tiredness, weight loss, stubborn and chronic coughs, night sweats and loss of appetite (Harvard University, 2010). Also, people with tuberculosis may have heavy sputum. An infection of the lungs makes breathing difficult, and a patient produces amphoric sounds when breathing. Tuberculosis is a highly infectious disease. It is spread through air. Individuals near an infected person are at a high risk of being infected. Normally, the bacteria are suspended in body fluid droplets suspended in the air when an infected person coughs, spit or sneezes. As such, any person who breathes that contaminated air is at a high risk of getting the disease. People at high risk include friends, family members, and health workers. Tuberculosis bacteria are highly resistant to medication. As such, it is important to detect the virus at early stages of infection. The treatment is done after a successful diagnosis that involves a test on the sputum, skin, and chest x-ray. Treatment depends on whether a person has only an infection or has active TB bacteria. Infected person may be treated using simple preventative drugs such as Isoniazid. However, advanced TB requires complex treatment. According to WHO, active cases of TB requires specialized drugs like Ethambutol, Pyrazinamide, Isoniazid and Rifampicin (2009). Tuberculosis medications are supposed to be taken accurately lest the bacteria becomes resistant to treatment. Tuberculosis is among the most deadly illnesses in the world and affects 2.3 billion people in the world (CDC). According to the American lung association, the threat of tuberculosis has been falling steadily from the 1990s (lung.org). In America, total deaths arising from the sickness has tumbled. In addition, most of the fresh infections are arising from immigrants. In fact, immigrant infections comprise 62% of total infections in the

Social Networks Research Paper Example | Topics and Well Written Essays - 1750 words

Social Networks - Research Paper Example It has by and large bridged the gap between willing buyers and sellers hence distance has proved to be no longer a challenge in transaction because it has enhanced communication between parties involved. Besides, the internet has proved to be man’s greatest innovative achievement and a popular instrument used in the performance of numeric functions and to enhance communication in the banking sector. Far from this, the internet which is synonymous to cyberspace has even dominated the health sector. It facilitates the distribution of power, enforcement of law and even delivers or retains very confidential information. However, since it is a public utility, the internet has caused much havoc to mankind because sometimes it has not been used for purposes for which it was intended. Some cyberspace users have abused the internet and have thus rendered it a vulnerable social, political and economic tool. Cyber threat has remained a top concern in most nations because of security conc erns. Research and study have found out that cyber security has continued to increase in intensity and sophistication with time. Its gravity has been witnessed everywhere hence this calls for great security concern in the entire world. As we can see, the ever-growing need to use internet services in our everyday life places individual users and even the government and organizations into a task of combating risk factors associated with fraud and sabotage of important information and sometimes the security threat to a person (Yar, 2006). Cyber space hackers have more than often hacked and tampered with confidential government and corporate information, which they use to cause security threats targeting not only government officials but also the common man. Cases of terrorism have continued to increase with time. This is alarming since massive loss of people and properties have been witnessed. The terrorists have routinely targeted business hubs and top government institutions. Victims of cyber attacks have reported that they have also lost massive investments in the process of cyber attacks. This is a matter of concern since no measures placed have proved reliable to curb this scam. According to a report by the National Academy of Sciences (2010), it has been noted that not even the renowned tech-savvy individuals and organizations have managed to stay immune to cyber attacks. Victims of cyber attacks have included important service providers like telecommunication companies, Google, travelling industries, defense and even the banking sectors. This shows that nobody is immune to threats caused by cyber attacks. However, some of the experts causing cyber threats have tried to justify their actions as not being in any way related to threat in the cyber. Some of the terms used to refer to these techs savvy that have sometimes used the internet for purposes other than what is intended have tried to create a distinction between themselves and real criminals. For inst ance, terms which have always confused computer users are hackers and crackers. As far as computer security is concerned, programmers have tried to bring out their argument that someone who tries to break into other computers is better termed as cracker because they use it for ill intentions. According to such experts, computer crackers are like criminals because they use the internet to cause security concerns to other internet users hence are sometimes called black hats. They cause security

Marketing & Entrepreneurship Essay Example | Topics and Well Written Essays - 3000 words

Marketing & Entrepreneurship - Essay Example Economic Factors Marketing management This is an important factor that constitutes to business success. An existence of an enterprise implies that there must be market for its products. Despite the competition from other producers an entrepreneur ensures efficient marketing skills to make profits. Effectiveness in product marketing is an important factor hat has to be put in consideration in any business enterprise. To enhance business success in marketing management, small scale business link up with both large and medium business enterprise. This linkage facilitates their supply of products hence it becomes easier to market the products. Production management For every enterprise to succeed, their must be a proper management in the production sector. The enterprise should have a well established source of raw materials. The cost of raw materials together with the cost of production should not exceed the cost of sales. A successful enterprise is one that always reaps profit from its sales. The department of production in any business must connect with the marketing department so as to ensure every item that is produced has direct or indirect market. Financial management Financial gain is always the driving force in any entrepreneurial investment. Therefore management of finances is a very important factor in any business enterprise. ... Therefore it can be argued that it is the financial capability of every entrepreneurial activity that measures its strength against the other as suggested by Ernst (2005, 165) Personnel management The department of the personnel is another factor that determines the success of any business enterprise whether small or large. Personnel management coordinates all activities related to workers in an organization. Its contribution to the business success is through how it handles the welfare of the employees. Offering the best to the employee in terms of salary, enough time limit of work and other incentives increases their motivation to work. The more motivated the employees are the more they increase production hence large sales. The increasing in sales indicates increase in profits and the business enterprise is said to be successful. Another factor relating to entrepreneurial success is the personnel skills and knowledge. Employees who have the necessary skill are capable of leading t he business to success. Political Factors Any business entrepreneurship occurs within a particular framework or political governance. Some of the political factors that affect business enterprise include: Political environment The political environment surrounding a business enterprise determines its operation and success. The current economic structure of the country may adversely affect the success of the business. For instance incase of an inflation the entrepreneurship is not likely to succeed. Favorable government incentives like loans to starting entrepreneurs, motivates them and they are likely to succeed. The economic strategies passed by the government such specialization on the area of production

Anguil Research Paper Example | Topics and Well Written Essays - 500 words

Anguil - Research Paper Example The company won the prestigious United States Chamber of Commerce award which s fitted to the best managed company in a given year. The company underwent major changes in its leadership structure in the year 2008 with Gen Anguil retaining his CEO positions but with fewer responsibilities. Chris Anguil who at the time was the Vice President in charge of Sales and Marketing became the President of the company while Deb Anguil who until then served as the Vice President of the Operations became the Chief Operating Officer. The company is being driven by its slogan which states, â€Å"Committed to Cleaner Air† that has motivated it over the years to develop a complete understanding of the processes of each customer as well as acquisition of a thorough knowledge on the application of the regulatory requirements. As a company dealing with thermal and catalytic oxidizers, the company offers a wide range of technologically advanced air pollution control products which are used in the abatement process of industrial emissions. Various forms of industrial emissions include Volatile Organic Compounds, odors and Hazardous Air pollutants. The company engages in the manufacturing of equipment, their installation as well as process analysis. In order to promote good customer relations, it ensures a 24 hour post sale service so as to ensure that their products operate effectively to the satisfaction of the customers. In offering industrial energy and heat recovery solutions, the company offers a unique blend of time-tested means of energy regulation as well as modern innovative approaches to such initiatives. The company designs manufacture as well as install energy recovery systems. The systems are geared towards reducing the operation costs of the customers, lowering their energy consumptions as well as maximizing on their revenues. The readily available energy recovery and heat transfer systems include air to steam exchangers,

Methedology in postgraduate education in UL Essay

Methedology in postgraduate education in UL - Essay Example ciples of accounting for postgraduates, human resource management, economics, business risk management and marketing (University of Limerick, Centre for Teaching and Learning, 2014). A student applying for any of these courses undergoes regular application process which involves online registration and submission of required details as prescribed by the university regulatory board. The learning process once admitted into the university comes in two folds. A postgraduate may apply for online learning described as O’Del (Open, Distance and Electronic Learning). In this platform, a student obtains all the course requirements and lectures online but merge at the end of the semester to fulfill the course requirement by taking final exams (Ebel, Mohr & Commission of the European Communities 2009, p. 77). On the other end, one may decide to leverage on the side of full time learning process, attending to lecture physically, submitting assignments one on one and not electronically or online. However, at the end of the learning period, the students merge for a common exams and evaluation based of syllabus coverage. Other than the theories taught in class, postgraduate students will undertake a two weeks training even study trip or business simulation program every semester. This is meant to enhance the student’s knowledge on writing dissertations which will eventually see them graduate from UL. The university operates of full time calendar with short interval holidays between the terms calendars. Each semester runs for a period of three months with one month holiday until the completion of the degree

Ethics paper on the goverment mandated vaccinations Assignment

Ethics paper on the goverment mandated vaccinations - Assignment Example etts, New-Jersey and Maryland the vaccination are imposed by the court’s resolution or by the law in force and in some states such laws are being considered. â€Å"During the last flu season, a hospital in northern Indiana fired eight workers who refused to get vaccines against the seasonal disease. According to several media reports, IU Health Goshen Hospital had instituted a policy requiring employees to get flu shots. Several employees balked at getting the shots and tried to seek exemptions. The hospital decided not to grant exemptions and terminated the workers when they refused to change their minds† (Alaniz, 2013). Such politics is very similar to the one in national socialist empires, Stalin’s regimes and communist China. When the officials are asked to lawful substantiation of such measures as forced vaccination of people even if they consider them to be a real treat for them and their relatives, they refer to the necessity of society protection (Poland et al, 2005). But if the vaccination is not so effective as it is stated by the officials why should we be afraid of unvaccinated people as vaccinated individuals were 100% protected? This question puts officials in difficult situation. The usual answer is: the small percent of vaccinated will not be protected enough and may be subject to risk (Hayward, 2006). Then it is necessary to recognize that the possibility of vaccination failure is higher than 5% and this leads to the following question: why should we be vaccinated if the protection is doubtful? Collective immunity is a myth as its conception is related to the natural immunity, which if formed in response (Carman et al, 2000). Many experts state that the best way to stop spread of flu is to stay home when we are sick and wear masks (Conley, 2013). Another question is that forced vaccination is the violation of human rights. Every person should feel free to make his/her own decision on the issue (Shugarman, 2006). Only parents can decide if to

The luggage holder Essay Example | Topics and Well Written Essays - 1000 words

The luggage holder - Essay Example Very little energy is used by the luggage holder and its applications. In addition, the luggage holder is manually operated, so it does not use any energy other than human effort. Since it requires human effort to operate, this makes it very sustainable and energy-friendly in the long-term. It is also renewable, efficient and non-polluting because it is natural energy. The only resulting impact identified so far is possible fatigue as a result of long periods of operation, which is also very negligible. Finally, all materials are as inherently safe and benign as possible. The luggage holder does not have any energy inputs or outputs though. When it comes to human capital, concept development, product design, assembly, and marketing are the labor-intensive stages of product development that require a lot of human capital. Creativity, innovation, knowledge, habits, skill, cognitive abilities, and social and personality attributes, are the human capital elements that will be in high demand in the design and development of the luggage holder. In regards to financial capital (monetary instruments), a lot of financial resources are required to fund the activities involved in the human capital aspect. When it comes to manufactured or real capital (made by people and their tools), there are steel works, plastic processors, manufacturing space (to support industrial production), assembly tools and machines, and other related forms of infrastructure will be required. The luggage holder does not require any natural capital (the Earths resources and bio-capacity). Very little natural capital is required to develop and sell this product. The materials required are obtained from very little natural resources, and do not interfere with the earth’s bio-capacity in any way. The product development cost is quite high, exact costs are not yet clear as per now. The product development

Alcoholic Beverage Essay Example for Free

Alcoholic Beverage Essay Alcoholism is a chronic problem that includes difficulty in controlling drinking, having to drink consistently to get physical independence, being preoccupied with alcohol, and continually using alcohol regardless of problems it causes (Brick, 2004). Alcohol should not be legal in U. S. because it is impacts negatively on health, family, community and on a person’s education. Alcohol drinking is like taking a drug. It is a form of drug addiction and drug abuse. Alcoholism is a worldwide problem that affects many people. Drinking alcohol has negative short and long term effects. Alcoholism has been associated with adverse effects on health, family, community, and education (Marshall, 2000). However, the effects on a person depends on particular factors such as how often and how much alcohol is taken, a person’s age, gender, when a person begun drinking and how long they have been drinking, their health, and family history (Begleiter amp; Kissin, 1996). It is in this regard that alcohol should not be legal in the United States. Alcohol is addictive, and people become addicts end up spending a lot of money on alcohol. It means that when they spend all the money they have on alcohol, they forget their families, and are not able to support the community in anyway. Some resort to stealing to sustain their drinking habit. Alcohol addicts sometimes engage in robbery acts to get the money for drinks. Community becomes at risk of destruction with excessive alcohol consumption allowed. When many people engage in excessive consumption of alcohol, education becomes at risk. People drop out of school, and illiteracy level increase in the community. In addition, the progress and development of any community depends on the health of its people. Therefore, when alcohol puts the health of its members at risk, community suffers in the long run. Alcohol affects both female and male differently. Men who consume alcohol, daily have an increased risk of health risks. Such men can experience cancer and heart disease in the long-term and low energy to sexual difficulties in the short-term (Brick, 2004). Men are more likely to suffer from liver cirrhosis, and have higher chances of being diagnosed with high blood pressure. Nearly 26. 6% of deaths among men of between 16 and 24 years old can be attributed to alcohol consumption. Men tend to be more dependent of alcohol (Marshall, 2000). Drinking too much alcohol damages a person’s body organs such as liver, brain, stomach, heart,and intestines. Brain is adversely affected because the brain cells die leading to loss of memory, learning difficulties, brain disorders, confusion, and problems with attention (Blane amp; Leonard, 1999). Liver is highly affected because of the great possibility of developing cancer in the liver, throat and mouth. The stomach may also acquire ulcers. Long-term drinking has also been linked to stroke and heart failure. The nervous system can also experience damage leading to behavioral and physical problems (Dasgupta, 2011). These problems affect health, family, community, and education in the long-term because of expenses associated with alcohol consumption, and possible treatment measures. Alcohol poses many effects on the body such as fertility. It reduces levels of testosterone. As a result, it could decline sperm quantity and quality, and lead to loss of libido. Alcohol is toxic to the testicles, and affects hormones. It could hamper production of sperms, hinder them from developing properly, and slow their movement towards the egg. Alcohol can also limit the liver from metabolizing vitamin A properly. It also depresses the nervous system, and could result in difficulty in getting and keeping erection (Peters, 2008). Many young adults do not realize that alcohol has a fattening effect. Alcohol can reduce the amount of fat that the body burns for energy. The human body makes several attempts to eliminate alcohol 1 / 3 very fast as it cannot remain in the body for storage. The process takes priority over nutrient absorption and burning of fat. In the long-term, there could be a serious damage in the appearance. Other effects include loss of hair in the body, breast enlargement, and withering of testicles (Dasgupta, 2011). Alcohol has also been associated with worsening of skin disorders such as rosacae. Rosacae skin disorder is responsible for expansion of blood vessels in the face making it redder. Heavy drinking can cause the appearance of pus spots and red bumps. It has also been linked to inflammation, pain and swelling in the joints. The effect is common among men of between 30 and 60 years old (Hannigan, Spear, Spear amp; Goodlett, 1999). As mentioned earlier, heavy drinking increases the chances of heart disease, liver damage, bone disease, cancer, anxiety and depression, and type II diabetes. Heavy consumption of alcohol also caused inflammation on the pancreas and irritates stomach. These effects indirectly affect family, community and education (Peters, 2008). Women are not safe from alcohol either. The body of women takes much time to process alcohol compared to men. Women feel more effects of alcohol than men even when they drink the same amount. The fertility of women is at risk with heavy consumption of alcohol. Women are high risk of acquiring breast cancer, and adverse impacts of the menopause. Women are advised in several studies to avoid alcohol when trying to have a baby. Alcohol disrupts menstrual cycle in women, and limits their chances of conceiving. These are bad effects on the body, and not good for family and community in general. Therefore, alcohol should not be legal in the United States (Hannigan, Spear, Spear amp; Goodlett, 1999). While drinking less alcohol may make one look good, heavy consumption causes bad skin, tired eyes, and weight gain for both female and male. It also interferes with people’s sleep. Heavy consumers of alcohol often wake up and feel like they have not had enough rest. Alcohol dehydrates the body and skin. It deprives the skin of certain vital nutrients and vitamins. Hence, it is not good for health. Alcohol is also responsible for much divorce among couples due to fights in the family, and lack of finances for family upkeep (Dasgupta, 2011). Alcohol is depressant. It means that alcohol calms people down, and slows down some body organs. With only 0. 05% level of blood-alcohol, a person begins getting dulled judgment, and his or her inhibitions get released. They then become clumsy and start having slurred speech with only a 0. 10% blood-alcohol level. At 0. 30% level of blood-alcohol, one nearly becomes unconscious. Any addition after that becomes extremely dangerous since at 0. 45%, one can get into a coma. Brain shuts down from 0. 70% and stop controlling the heart, breathing, and one may end up dead. Other short-term effects include blurred vision, blackouts and insomnia. These can lead to injuries, accidents, and even death. Drinking alcohol also causes hangover in the next morning, which is associated with nausea, headaches, heartburn, fatigue, thirst, and dizziness. There are many side effects of alcohol (Peters, 2008). Conclusion In conclusion, consumption of alcohol should be reconsidered in U. S because of its adverse effects on health, family, community, and education. Alcohol should only be taken when necessary. The side effects are adverse and continue to destroy people across the world. Therefore, alcohol should not be legal in the United States because it is impacts negatively on health, family, community and on a person’s education. References Begleiter, H. , amp; Kissin, B. (1996). The pharmacology of alcohol and alcohol dependence. New York: Oxford University Press. Blane, H. T. , amp; Leonard, K. E. (1999). Psychological theories of drinking and alcoholism. New York [u. a. : Guilford Press. Brick, J. (2004). Handbook of the medical consequences of alcohol and drug abuse. New York: Haworth Press. Dasgupta, A. (2011).

Porters Five Forces Study of Starbucks

Porters Five Forces Study of Starbucks Executive Summary: Given case study maps the situation of the company in 2009. In this assignment we will date back to a timeline of about 25 years and see how Starbucks developed their business. We will also see the strategies applied and the present situation of the company with the application of Porters five competitive forces. Finally we will have a look at the future recommendations to reap a profit from the business Part: 1 Starbucks Coffee Company Founded in year 1971 First headquarter in Seattle USA Business in 37 countries Expansion started 1982 with Howard Schultz joined Starbucks has evolved from being a $.50 million business to a business that worth $6.4 billion Howard Schultz is the Chairman, President Chief executive officer History: 1971: Pike Place Market in Seattle was the first place where Starbucks store was settled 1982: Howard Schultz joined the company as marketing and retailing head 1985: Espresso bar concept 1987: Schultz purchased Starbucks and merged his business Giornale Coffee House with Starbucks 1987: Expands Business in the American market by starting outlets in British Columbia and Chicago 1992: With a business comprising of 165 outlets, Starbucks gets listed with its first public stock offering. 1996: Expands business to Japan, Tokyo was the first place. 2003: Starbucks expansion continues at a robust rate and it translates into a company with 6400 outlets worldwide. 2008: Global economic meltdown resulted loss in profitability, Starbucks decided to shuts down 600 outlets across the world and also exits the Australian market. Howard Schultz Chairman, President Chief executive officer VISION, OBJECTIVES AND MISSION Vision Statement: To establish Starbucks as most familiar and appreciated brand in the world and become a national business with values and guiding principles that employee could be proud of The vision statement clearly describes the dream or the future of the company that is to be the worlds most well known coffeehouse and also to be the most appreciated and positively graded brand by all levels of people around the world. The company also focuses its vision to employee satisfactions, so that the employees will be happy. Objectives of Starbucks: Is to grow by making employees feel valued Is to recognize that every dollar earned passes through employees hands The Six principles are: Respect and dignity Quality Diversity Profitability Satisfied customers Commitment Corporate Values and Business Principles: Building a Company with Soul Opposing Franchising because of Quality Control and Culture Only selling coffee beans without artificial flavors. Satisfy customers by all means. Employees contribution and involvement in making Starbucks a better company Corporate Social Responsibility: Establish the Starbucks Foundation in 1997 A major contributor of CARE, worldwide relief and development organization (Health, Education, and Humanitarian aid) Participate in local charitable projects. Provides financial support to community literacy organizations 2004 EnviroStars Recognized Leader Award for its community service and environmental activities Value Chain: Starbucks do not have a vertically integrated supply chain. It always works at increasing its relationship with its suppliers through the fair trade initiative Success Factors for Starbucks: Factors which helped Starbucks to gain success Starbucks were the first coffee makers in business Starbucks started their operation in the year 1987 under Howard Schultz Within the first five years they had 150 stores. First specialty coffee retailing chain in the market. First move advantage gave Starbucks a reason to establish a value proposition within customers and comes with a unique brand positioning. Profits were huge enough to allow them invest in their expansion plans. Market Research: Starbucks performed comprehensively study for expansion and enter into new markets. 1991 was the year in Starbucks moved to California resulted after a lot of market research. The reason why California people adapt quickly to changing lifestyle and that is the reason of choosing California. Employee Satisfaction Motivation: Starbucks played a major role in this aspect. Highly motivated and well trained staff resulted the high level of employee satisfaction. Starbucks offered health benefits to their employees for employees who worked more than twenty hours in a week. Starbucks Strategies (1983- 2008) Schultz restored the old and honest employees of Starbucks to give the best service to the customers. Dave Lawrence was hired as a executive vice presented and charged with leading operation, finance and human resources. In order to increase the market share, Starbucks has differentiated itself in providing a unique experience to its customers. In order to create a unique value proposition, Starbucks have created stores with specific themes. Secondly they have a focus on different flavors of beverages to suit peoples needs. Starbucks have developed the market for specialty coffee industry for America. In this context, Starbucks have created brand awareness and henceforth have created a demand for coffee stores amongst American population. Therefore, they have taken coffee from a commodity market to a specialty item. New logo was invented to match the culture of the Starbucks and Giornale. New espresso machines were equipped and look more Italian than old world nautical Chicago store opened in October 1987 as per expansion strategy Identifying inability of the customers for having a cup of coffee in the winter season in Chicago, Schultz solved the problem of freshness and quality assurance by putting freshly roasted beans in special flavor lock bags that used vacuum packaging technique. Portland, oregon was the next market the company entered. Entered in L.A in late 1991. Opened 15 new stores in 1988, 20 in 1989, 30 in 1990, and 53 in 1992, producing a total of 161 stores in US. Also went for franchising concept to retrieve the cost for new store expansion. In order to make Starbucks a great place to work Schultz accepted to expand healthcare coverage to include part-time workers. To oversee the expansion process Starbucks created zone wise vice presidents to direct the development of each region and to implant the Starbucks culture in the newly opened stores. Starbucks had created a new subsidiary, Starbucks coffee international, to orchestrate overseas expansion and build the Starbucks brand name globally via license. To accommodate its strategy of rapid store expansion. In august 2002 Starbucks teamed up with T-mobile USA, the largest carrier-owned Wi-Fi services, to experiment with Providing internet access and enhanced digital entertainment to patrons at over 1200 Starbucks locations. Part 2 Starbucks Performance (Fiscal 2009 Annual Report) Stores Open : Store Sales Growth: (1) Store openings are reported net of closures. (2) Of the approximately 800 total US stores identified for closure, 566 stores and 205 stores were closed in fiscal 2009 and 2008, respectively. (3) Starbucks restructured its Australia market by closing 61 stores in fiscal 2008. Of the approximately 100 International stores (incremental to the Australia closures in fiscal 2008) identified for closure, 41 stores were closed in various markets in fiscal 2009. Net Revenues: Operating Cash Flow Capital Expenditures: Company revenues decreased from fiscal 2008, primarily attributable to a 6% decline in comparable store sales, comprised of a 4% decline in transactions and a 2% decline in the average value per transaction. Foreign currency translation also contributed to the decline with the effects of a stronger US dollar relative to the British pound and Canadian dollar. The weakness in consolidated comparable store sales was driven by the US segment, with a comparable store sales decline of 6% for the year. The International segment experienced a 2% decline in comparable store sales. The Company derived 16% of total net revenues from channels outside the Company-operated retail stores, collectively known as specialty operations. The decrease in Foodservice and other revenue was primarily due to the softness in the hospitality industry. Schultzs Actions in 2008/2009 Retrained all the store employees They reduced operating costs by $600m per anum Simplified the product range They Closed 1,000 worst-performing stores Introduced Fairtrade coffee Started advertising Porters Five Forces Potential entry of Competitors (Low). Differentiation: Coffee industry companies tries to achieve differentiation in their service qualities through stores ambience, staff and complimentary products. Hence it becomes difficult for new players to imitate the existing business models. Potential development of substitute products (Low) Companies such as Pepsi and Coca Cola have been a threat to specialty coffee retailing from a substitute perspective. In the current situation this threat has been lowered considerably Bargaining power of suppliers (High) Trade Policy Farmers associations that practice the fair trade policy. In US this initiative is called the TransFair initiative. Users of these are certified coffee beans are regarded as more reputed by customers and hence most companies such as Starbucks are forced to buy from these farmers. This increases the bargaining power of suppliers. Differentiation Because of the taste differentiation companies need to procure an assortment of different varieties of coffee beans from different specialized farmers. This results the increase in the bargaining power of suppliers. Rivalry among competing firms (High) It faces tough competition from local baristas due to price factor. Starbucks is priced higher than these local players. Starbucks faces stiff competition from McDonalds, Dunkin Donuts and a number of players. Overall the industry is growing but at a slow rate and there are lot of players. Cost: In terms of switching cost, consumers do not pay a high amount when they needs to switch their preferences from Starbucks to other coffee shops. Starbucks have lost a number of its customers because of the high prices. Customers opine that they get the same coffee in other places at lower prices. Bargaining power of consumer (Moderate) Loyalty Programs: Repeated purchases from a single customer become guaranteed customers are bounded to the organization through Loyalty Cards Low Switching Cost It usually plays a negative factor to the companys growth by increasing the bargaining power of buyers. SWOT Analysis Strength: Starbucks has proven to give an outstanding performance in customer service and experience. It has its own unique playback songs system which can be used to listen to your choice. Starbucks have changed coffee to a recognized beverage. One of the major strategies of Starbucks is that it has never used expensive television advertising campaigns or brand ambassadors to advertise, instead it has relied more on its universally present cafes, word of mouth publicity and the ambience of its stores. It has maintained a high level of service through which it has achieved a consistent level of customer satisfaction. Weakness: Customers are never loyal to a single store and keep on changing their stores, because when ever Starbucks enters any international market it opens a large number of stores within close vicinity Sales of individual stores are never stable. Because of the recent recession, the levels of same store sales and margins have come down. The fourth quarter results have shown a loss of 70% in the companys net income and share prices have fallen by 33 cents. There has been a closure of 600 stores and lay off for 6700 stores. Opportunities: Along with coffee Starbucks has also branched out to produce DVDs, CDs, t-shirts and other proprietary food product offerings. The market for these products has grown considerably and gives a great opportunity to Starbucks for leveraging their brand. Starbucks should also look at exploring some of the emerging economies in South Eastern Asia such as India where the economy is stable. Threats: The economic recession is a threat for Starbucks since they had to close down a large number of stores leading to declining profits and large level of unemployment. McDonalds and Dunkin Donuts serve high quality green coffee also which is an impending factor on Starbucks growth. Starbucks is facing major challenges from competitors such as McDonalds and Dunkin Donuts. Strategic Synopsis: Starbucks faces an extremely challenging fiscal 2009 due to the ongoing economic slowdown. It noted that its customers may have less money for discretionary spending as a result of job losses, foreclosures, and bankruptcies. Any resulting decreases in customer traffic or average value per transaction will negatively impact the companys financial performance as reduced revenues result in sales de-leveraging which creates downward pressure on margins. The company also said it expects negative comparable store sales for fiscal 2009 and that additional restructuring measures may be needed in the future if Starbucks is unable to improve its financial performance. PART: 3 Customer, Market, Market Segment: Customer Segment: Its is well known for its coffee as well as the relationships formed with its customers. This targets college students and business people in general, as well as individuals. Target Market Starbucks us always adult -focused and look forward to aim to connect with their customers, childrens and communities through different types of advertisements tactics. College age group and post graduates are the big growing market. Market Attraction Targeting adults and young adults is a good mechanism for Starbucks because this age level has the same interests as the foundation that promotes arts, culture, education, and the environment (starbucks.com). The company satisfies their customers through their advertising, support programs and, of course, their coffee. Resources and Capabilities A: Resources, capabilities and Strategic Assets: Every company or organization needs and owns certain resources, capabilities or competencies and also assets which are a necessity to endure and prosper globally. The resources consist of: Creating Competitive Edge Intangible Resources Recipe Employee relationship Large customer base Reputation of products and services Tangible Resources Large number of outlets Machinery equipments Operations in 37 countries RESOURCES CATEGORIES STARBUCKS RESOURCES PHYSICAL RESOURCES Operation in 40 countries Conventionally taste and environment. Effective segmentation. Supply chain management. Large number of outlets. FINANCIAL RESOURCES Turnover of  £46.56 billion in 2009. Gross margins of  £4.13 billion in 2009. Profit of  £2.1 billion in 2009. HUMAN RESOURCES Greatly competent labour force. Young and prosperous. INTELLECTUAL CAPITAL Reputation for excellence Brand image built as taste, environment. Strategic capability of Starbuck: CATEGORIES STARBUCK RESOURCES THRESHOLD RESOURCES solid supply chain. Young and affluent workforces. THRESHOLD COMPETENCIES Quality. Reliability. Dealings and relationship with its employees and customers. UNIQUE RESOURCES Hi-tech coffee machines equipments. Extraordinary labour force CORE COMPETENCIES Technology. Speed of production. Known as The Best coffee provider B: Structure, Culture and organizational knowledge There are very less companies who can boast to be as consistent as Starbucks in terms of attracting the customers which is always adjusting itself for the demand of the time with seamless quality and efficiency. The adjustment which is the company is willing to accept all the time is what makes it different from the rest. Their philosophy of the Starbucks is to provide product which are marvel of taste but also come with value and satisfaction. B: STRATEGIC CHOICE Identification of Strategic Options Ansoffs Product/Market Matrix Considering the approach of STARBUCKS they should continue to go with what they are doing currently. It means stick to what they do best. I think that they do need to enter new markets for themselves and in particular ASIA. Currently STARBUCKS is not one of the most commonly used or known brands in ASIAN region. To pin point the region the areas to focus must be China and South Asian markets. STARBUCKS has set its sights on Chinese Niche market with view of the massive growth in Chinese economy and the wealth generated. Working in China would also mean that they will be able to work with the best available technology and also the fast growing consumer market that exists within China. Other region of interest can be South Asian emerging markets and in particular India who are enjoying a massive boom in economy and also buying power. In my opinion the strategy used needs to be Business to Customer or B2C as this strategy has already served STARBUCKS Group very well in the past. The benefit of the strategy will be that it will be Product driven and will also maximize the value of the transaction and plus they will have larger target markets. This will also ensure that there will be a single step buying process and will enhance brand identity and also the brand image will also work as an extra helping hand for the company. B2C strategy will ensure the brand loyalty and also will promote emotional buying decisions which will base on status, price or may be desire. RECOMMENDATIONS FOR ACTION Starbucks should continue with its operation in the growing economies and markets and diversify themselves to new markets where ever possible. As most of markets of Europe and America are at a stage of maturity, the realistic option for growth is diversion to new markets. The markets of Europe and America are older and also are very established for the Starbucks and it also has developed a brand loyal segment of customers behind them. That is the reason they need to consolidate the work they have so far put in to the emerging markets and consumers. To put the strategy into action STARBUCKS needs to consider the below stated aspects so that the transition or change over to new markets is as smooth as it can get. The timing is one of the major aspects which need to be taken care off or estimated beforehand. Since company already has its plants based in INDIA and CHINA; they still need to develop them further to enhance production and meet the growing demand of a growing market and also a growing consumer base. The time it will take for them to either acquire or go into further and further of franchise growth model. The other important type of strategy in which STARBUCKS has been largely successful is by creating their 100% subsidiaries in the emerging markets so that it becomes a strategic asset for the company and would usually mean that it will be cost effective manufacturing by producing it in developing countries; which means that they will have relatively less expensive labour at their disposal in comparison with already developed countries and markets. The constraints for company can be the rise in prices of raw materials will definitely impact pricing and positioning of the brand. They will also have to work extensively to keep up to date with taste of consumers and also their preferences in terms of product. Another factor can be the potential of the markets suggested will definitely appeal to the competition and it might trigger a price war and fierce rivalry amongst the industry players. The fluctuation in international business will also affect STARBUCKS in particularly the international currency market. This strategic plan may be able to help STARBUCKS achieve a safer journey ahead and they will be able to sustain a strong foothold in the world. Starbucks should continue to open new locations worldwide. Starbucks is extremely dependent on its domestic success, and yet has a variety of countries it has not explored opportunities in. However, it is recommended that Starbucks tread lightly and with caution, insuring proper social and cultural analysis before plunging into a country. This is apparent in the fact that Starbucks was forced to close three retail stores in Singapore last year.   

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