Unorthodox Writing Tips

Unconventional Writing Tips Unconventional Writing Tips In the event that you’ve ever gazed at a clear page, attempting to invoke the correct words and coming up void, you’re not the only one. Numerous journalists, in spite of being energetic about their specialty, discover the creative cycle long and testing. Here are some strange composing tips to attempt when you’re stuck on a clear page: Start in the Middle A bit of composing commonly begins with a presentation, trailed by the body of the piece and the end. In any case, numerous scholars stall out toward the start. You can maintain a strategic distance from this by going directly to the body of your piece and composing the presentation last. Take as much time as necessary In the event that motivation escapes you, maybe it’s time to put the pen down for an hour or two and permit your brain to meander. Attempt an action that doesn't require a lot of mental exertion. A lengthy drive, a walk, or in any event, cleaning the house can get your expressive energies pumping. Come back to your work area when you’re feeling less baffled. â€Å"Ramble on!† On the off chance that this is your first draft, have a ton of fun. Let the words stream without control and compose whatever rings a bell. This gets you â€Å"in the zone† and puts words on the page. You’ll be astounded how acceptable some of them may be. Late, you can alter and refine your work. Recollect the Purpose of Writing To establish the best possible pace, you should comprehend what you need to achieve. There are three primary objectives of composing. Knowing into which classification your piece falls will assist you with keeping on target. These are: To Inform Informative pieces teach the perusers. They are clear, exact, and (in particular) objective. In the event that you’re writing to advise, forget about your sentiments and focus on what matters. To Express Expressive pieces build up human associations, pass on qualities, and add to culture. They for the most part have a progressively easygoing tone and structure, and frequently incorporate sentiments and feelings. To Persuade Persuasive pieces are a genuine type of composing intended to change the psyche of the peruser, or possibly make them question their position. An influential piece must be upheld by dependable sources and dependent on realities to keep up its believability. Since time is running short and exertion composing requires, even proficient journalists experience writer’s square now and then. Don’t be excessively hard on yourself on the off chance that you stall out. Utilize these tips, or get help from proficient scholars and editors to finish your piece. On the off chance that you need assistance composing papers, is here to help. You can get in touch with us at (647) 436-7280.

Biology Dissertation The Key Points to Consider When Writing

Science Dissertation The Key Points to Consider When Writing One of the most testing scholarly assignments is to compose a paper. It is mind boggling, and you ought to be completely occupied with the way toward composing. It turns out to be significantly progressively mind boggling if the issue is troublesome or not intriguing to you. In this way, it is very imperative to pick the point you like. A science paper might be somewhat problematic. Regardless, in the event that you have a decent order of the control and expertise to create it appropriately, you will make progress. Here are some fundamental prompts on the best way to finish all phases of your thesis in science: Compose the cover sheet. It ought to contain the exposition title, the name of a specialist, the principle purposes behind accommodation of the task, the name of the instructive organization, department’s name, the month and year of distributing. This is an extraordinary page, which contains your thankfulness to those individuals who helped you to create your examination in science. Theoretical. This is an obligatory component of any paper, which covers the significant purposes of the examination. Its length ranges from 100 to 150 words. It ought to incorporate the foundation of your point, the target of the exploration, its results, and chapter by chapter list. Brain that all parts and sections should be counted. Presentation. This area ought to ignite a craving to peruse your thesis. Make it infectious, show the significance of your examination. Execute a postulation and plainly portray your principle reason and target to direct an investigation. Educational sources. This segment isn't mandatory. This is the quantity of articles you’ve read that are identified with your paper. By and by, it will just profit your undertaking. Accordingly, your perusers will see the entire size of your work and what sources you utilized. Procedure. You can't avoid this area. A scientist should show the techniques that were utilized to lead the investigation. Additionally, you ought to clarify why you have favored these strategies. Results. The following stage is to speak to the results of your examination. Assess the data you have gotten. Utilize all related measurement figures. It’s essential to recall that an analyst ought not give his/her closely-held conviction. Save it for the segment committed to the conversation. Conversation. This part brings together the results of your exploration question. You ought to break down and assess the discoveries you have gotten during the investigation. This is the point at which you should in like manner express your own conclusion about the acquired outcomes. Proposals. Presently, you should offer a few suggestions in the respect of the acquired outcomes. Decipher your discoveries and remark on the fate of your venture. Point out the plausible upgrades in the field you have chosen. Reference index. This is the full rundown of all data assets that were utilized and have added to the improvement of your task. These segments are the unavoidable pieces of the whole research venture. You should discover how to achieve each rapidly and viably. Pay attention to this issue and don’t neglect to utilize a few realities to make the paper progressively appealing. The last assessment of your science thesis is subject to each stage. Make a compelling diagram and complete each phase thus.

MA Handling A Carve-Out

MA Handling A Carve-Out MAs are not the easiest processes to carry out. There are many facets to pay attention to and so many aspects to consider. It goes without saying that not all MA efforts become successful, and much of the reason for the failures can be pinned on mishandling or wrong steps undertaken by the parties involved in the merger or acquisition.When it comes to carve-out transactions, they actually involve more than what meets the eye, and many MAs have become unsuccessful because they were not able to handle carve-outs properly. © Shutterstock.com | Monkey Business ImagesThis time you will learn about 1) what is a carve-out, 2) steps on how to do carve-outs, and 3) strategies for a successful carve-out.WHAT IS A CARVE-OUT?The simple definition of a “carve-out would be the “partial divestiture of a business unit”. In the MA context, it is the sale or divestiture of a business unit or division from a company. It is certainly different from your usual straightforward merger or acquisition transaction (which are essentially total or complete divestiture), since it is more complex and has a lot more areas that need attention.There is a general impression that a carve-out means the outright sale of a business unit or division. But that is not the case. The company divesting that business unit will still retain an equity stake in it â€" and a share in the profits â€" even after the divestiture.There are two types of carve-outs: equity carve-out and spin-off.Equity Carve-Out: As the phrase implies, this strat egy involves the sale of equity or ownership shares in a division or unit, allowing the business to have a cash inflow up front. This is often employed by businesses that are:planning for a total divestiture in the future, but still needs cash presently to sustain its operations;unable to find a single buyer that can afford the acquisition cost of the entire business; orunwilling to let go of complete control over the unit.Spin-off: Instead of selling just the shares of the business unit, the spin-off involves having the business unit become a standalone or independent business, with its own shareholders and management. However, just like the equity carve-out, the business may still have equity stake that is owned by the original company it was spun off from. In addition, the shareholders will come from the current pool of shareholders of the original parent company, since they are the ones given priority when shares in the new independent company were spun off.Advantages of using a Carve-Out StrategyThere are many reasons why businesses prefer to employ a carve-out strategy instead of selling or purchasing an entire business or company.It is a way for the selling company to capitalize on a business division or unit, especially if that unit or division is not part of its main operations, and it is not really making money off it. The parent company will still earn profits from it, even more than the buyer, since the parent company usually retains controlling interest.Compared to a complete sale or a full initial public offering (IPO), a carve-out will save companies from paying capital gains taxes once they divest a unit, division or subsidiary, which are meant to be spun off afterwards anyway.One fear of companies is that their business unit may be taken over by a rival or direct competitor. By resorting to carve out, they can still maintain control of the unit, and prevent competitors from taking over.Carve-outs are useful in the sense that it gives the new i ndependent companies a chance to become more stable before they are fully exposed to the competitive business landscape. By the time it does get exposed, it will have already gained solid footing.Areas of Focus in a Carve-OutBefore a carve-out can be fully initiated and the parties move on to the transition stage, it is important to identify the areas that need the most attention. The main areas of focus are briefly discussed below.Payroll: If you are the one acquiring the business unit, one of the first things you should take note of is the continuation of the payment of salaries or wages of your employees or personnel. Check that the unit has a payroll account to handle the paychecks that will be given to the employees in the upcoming pay periods, particularly during the transition.Employment paperwork: Lay-offs often come with the territory when it comes to mergers and acquisitions. Some employees may be fired, or new ones may be hired. Do not let employment issues and mishaps ca use a delay in the operations of the carved-out unit. Make sure all the paperwork regarding employment are taken care of, especially when it comes to those who are going to be separated from the company, and those who are fired by the original owner, but will be rehired as an employee of the new company. Having a solid human resources management staff will definitely ease the load.Management: You have to identify the person in authority that will handle or run the carve-out. If there is no suitable person who can do it, then you might want to consider hiring new management to make it work.Accounting: Take note of the accounting system being used by the original company in the business unit that is being carved out. You would have to coordinate with the accounting department to ensure that all accounting issues and problems have been settled. Is the accounting software or program part of the carve-out deal, or do you have to bring in your own accounting team with your own accounting program?IT and communication systems: IT will play a very important role in the carve-out, so you have to check what IT systems are in place, and if the company has a working communication system. Ownership of the IT systems must also be established. Do they belong to the original owner? Do they come with the deal? Or do you have to set up a new system and even install new software?Overhead: There is a need to do an accounting of the applied overhead, which covers all the services and processes that the original owner of the business unit performed. Buyers really cannot do away with the applied overhead, since it is a given that the original owner will have performed several functions, which you will take over once the carve-out has been effected.STEPS TO CARVE-OUT FOR SELLERS AND BUYERSErnst Young prescribed four steps each that buyers and sellers have to take in order to fully maximize the value of carve-outs.For Sellers:Step 1: Understanding the motivation of the buyer in divest ing of a business unit or division. This is so that sellers will know how to market the assets or unit to be carved-out to the potential buyers. Buyers have various reasons for eyeing a business unit for purchase, and you have to clearly be aware of what those reasons are.This can be simplified by classifying the buyers or acquirers into two:Corporate strategic buyers are those that are selling because they are looking for assets that will complement their business, and the carved-out assets are meant to be integrated into their current operating structure. These types of buyers are looking to add to their existing businesses by acquiring additional units or subsidiaries which they plan to operate as a going concern. Thus, sellers are more likely to market the business unit by highlighting on its growth potential.Financial buyers are those that want to acquire a business unit with the plans of continuing its operations, or to spin it off into a standalone, independent company. The b est example of these buyers are the private equity firms that purchase equity stakes in a business, spin them off into a standalone company, operate it and turn it into a profitable venture, and eventually sell it off at a higher cost. Sellers will then highlight the unit’s ability to make a successful turnaround and churn out the profits in the future because, naturally, buyers will want to acquire a business unit that will give them higher gains in the future, once they sell it off.Step 2: Preparation of pro-forma carve-out financial statements for valuation, funding and compliance purposes. There has to be a clear indication of how much costs will be incurred in the carve-out process, and immediately after the carve-out. Buyers would also want to see if they are acquiring a business unit or division that appeals to them, especially on a financial level.Step 3: Maintaining transparency when it comes to costs.As a seller, you must be fully aware of the value of a potential carve- out in order for you to be able to package your carve-out assets and market them better to potential buyer. All valuation factors must be taken into account, especially the after-tax effects, which are often overlooked.Step 4: Considering the impact on the remaining business. You have to identify the potential effects â€" particularly the negative one â€" which the remaining divisions of the business will go through after a unit has been divested or sold off. Will it affect the operations of the other units? Will it decrease the profitability of the other divisions? Will the costs increase as there are lesser units to carry the burden?For Buyers:Step 1: Know what you are getting. This involves looking into the components of the unit you are acquiring â€" the assets, the accounts, the liabilities and other encumbrances, the manpower or personnel involved, and others. They should also be cognizant of the risks and challenges that come with the carve-out. This way, they can make adjust ments to their plans, as well as come up with solutions to any possible problems that may crop up in the process.Step 2: Perform cost evaluations. It is not a good idea for buyers to simply pay up once the sellers name their price. You have to conduct an assessment of the cost presented by the seller. Get an inventory of the services utilized in the carve-out as the cost equivalent will be significant in the valuation of the entity.Step 3: Always be ready. While it is true that the parties involved may have mapped out a timeline or a schedule, there are still high probabilities of curveballs being thrown their way halfway through the process. That is why it is imperative that steps are taken to ensure that business processes can be performed at a moment’s notice.Step 4: Pay attention to the details of the transition agreement to ensure that the integration of the assets acquired is smooth. The details that must be noted most include the accountable people and their respective acco untabilities, whether it is on the services that have to be performed during the transition, or the costs that are going to be incurred.STRATEGIES FOR A SUCCESSFUL CARVE-OUTFollowing the steps strictly is not a guarantee that a carve-out transaction will be successful. There are strategies that can be employed in order to make it work, and work very well.Having a set of guiding principles for both buyer and seller in place.As mentioned earlier, there are different motivations on the part of the buyer on why it is acquiring a business unit or subsidiary. Those motivations will matter greatly once the transition negotiation stage is entered into. There is a need to develop guiding principles that both parties will agree on, in order to avoid conflicts, deadlocks and bigger problems later on, which could possibly result in the carve-out process being delayed or, worse, derailed.The guiding principles should focus on, at least, the following problem areas:Nature of services: This answer s the “what” element. What services will be adhered to? In some cases, they focus more on the function of the service instead of the nature. That is too broad, and can cause confusion later on. By defining the nature of the services, (such as “accounts payable” or “accounts receivable” instead of the finance or treasury function), things will be slightly more pronounced and easy to identify.Fees and cost calculations involved: In connection with the services that will be provided, there should also be guidelines on how much these services would entail. What are the fees applicable? All too often, conflicts will arise on the valuation of these services, so it is important to come to an agreement early on. In the same way, transactional and other costs will also have to be computed. The guiding principles should also expressly indicate the basis for calculating these costs, both for transparency and uniformity.Timelines: Not all carve-outs take the same amount of time. Som e are more complex than others, depending on a lot of factors, such as the nature and size of the business unit, and other internal and external considerations. The timeline that will be agreed upon must be deemed reasonable and realistic by both parties.Performance standards: Similarly, the performance standards that will be used should also be reasonable. Parties tend to be quite demanding, without taking into account actual historical performance and possible problems that may crop up. One way to set reasonable performance standards is to look at historical data or perform benchmarking.Preparing a clear destination in mind.You know what you want to happen with the carve-out; that means you must already have a clear destination in mind. There is a need to clearly draw a picture of what the end result of the carve-out will be. We have already stated the areas of focus during carve-out. Those will also come into play here. Defining your destination is done by considering:Assets, spe cifically those that will remain as assets of the business unit that has been acquired. This is also to closely identify the assets that will remain in the possession of the parent company.Employees, specifically those that are critical to the carve-out. Who will have to stay with the parent company? Who will be most beneficial to the acquired company? What are the positions or functions that will be left empty and will need filling up during and after the transition?Financials, or the state of finances of the acquired company. The key point here is whether the financial statements are truly representative of the financial performance of the company, particularly when it starts operating independently.Services. During the transition, the seller is still expected to render some services, but it is also possible that the buyer will, in turn, provide services of its own. Identify what these services are, who will provide them, and how they will be provided.Getting All the Right Resourc es Needed.You have resources; the question is: are they enough? Or, more importantly, are they the right resources?Additional resources must be considered, not just funding and manpower. Outsourcing has certainly become a popular option for companies, especially when they need a third party with specific expertise on the industry that the business belongs in.The complexities involved in a carve-out make it a daunting prospect for businesses. However, it has far more enduring positive benefits in the long run, which is why we can expect to see it as an integral part of MA transactions in the future.

Argumentative Essay Generalist Social Work Practice

Position Paper Two: Generalist Social Work Practice Dating back to the end of the nineteenth century and the beginning of the twentieth century two women who impacted the field of social work and its beginning were Jane Addams and Mary Richmond. These two ladies pioneered something that later became one of the most influential evidence based practices that has helped to bring social justice and social support to communities, individuals, and groups. The area of social work later developed the generalist practice model to serve as the basis for the profession. The field of social work instills an academically practice based form of learning while promoting social change and growth, social cohesion, and empowerment to individuals of†¦show more content†¦Lastly the fourth premises of Generalist Practice are the duty to uphold research findings and apply them toward social policies (Miley et al., 2017, p. 7-8). As previously noted Generalist practice is used within a wide range of systems of different intervention levels. Th e levels of intervention within general practice are Microlevel, Mezzo level, Macrolevel system intervention, and the professional level intervention (Hall, 2008). The primary focus of Microlevel systems intervention is the duty to work with families, individuals and groups. In addition, the Mezzo level systems intervention places its focal point upon organizations and more formal groups. Similarly, the Macrolevel intervention concentrates on the issues involving communities or society in general. In final, the Professional level intervention prioritizes the issues within the social work profession itself (Miley et al., 2017, p. 7-9). Due to the diverse populations and vulnerable groups that Social Workers work with on a day to day basis it is important for them to understand the different levels of intervention to properly assist clients with the necessary framework for addressing issues of concern (Gelman Mirabito, 2005). There are also various models that can be used to pr omote an empowering approach toward practice. One of the models used mostly within the General Practice is the problem-solving model. Problem-Solving Model The problem-solving modelShow MoreRelatedStephen P. Robbins Timothy A. Judge (2011) Organizational Behaviour 15th Edition New Jersey: Prentice Hall393164 Words   |  1573 Pagesobtained from the publisher prior to any prohibited reproduction, storage in a retrieval system, or transmission in any form or by any means, electronic, mechanical, photocopying, recording, or likewise. To obtain permission(s) to use material from this work, please submit a written request to Pearson Education, Inc., Permissions Department, One Lake Street, Upper Saddle River, New Jersey 07458, or you may fax your request to 201-236-3290. Many of the designations by manufacturers and sellers to distinguishRead MoreLibrary Management204752 Words   |  820 Pages . . . . . . . . 396 Basic Steps in Team Building . . . . . . . . . . . . . . . . . . . 398 The Roles People Play in Teams . . . . . . . . . . . . . . . . . 399 Team Communication . . . . . . . . . . . . . . . . . . . . . . . . . 401 The Future of W ork Teams in Libraries . . . . . . . . . . . . 401 Contingency Approach to Leading . . . . . . . . . . . . . . . . 402 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 xiv Contents Section 6: Coordinating 18—Measuring

Business Analysis Business Enterprise Essay - 1881 Words

Business enterprise is rapidly turning out to be increasingly prominent as more individuals are hoping to pick up a touch of opportunity from their vocation, rather than working for a conventional business or organisation, numerous individuals are stretching out into the universe of enterprise and turning into their own particular supervisor. (Sedlar, 2015) An entrepreneur begins their own particular business and benefits from it, as business visionaries, they are pioneers, willing to take risks and produce new thoughts to make remarkable and possibly beneficial answers for cutting edge issues. This development may bring about new associations or rejuvenate mature associations because of an apparent opportunity. Entrepreneurial exercises contrast considerably relying upon the sort of association and inventiveness included. (Sedlar, 2015) Business enterprise ranges in scale from solo tasks that can even include the entrepreneur working just part-time, to significant endeavours that ma ke numerous openings for work, a few high-esteem entrepreneurial endeavours look for investment to raise capital for building the business. However, in the UK, unemployment increments in a retreat that are driven by ascends in the partition rate. Another deterioration of unemployment flow is conceived that does not oblige unemployment to be in relentless state at all times. (Entis, 2015) This is critical on the grounds that low UK adjustment rates, suggest significant deviation of unemploymentShow MoreRelatedSwot Analysis : Business Enterprise2101 Words   |  9 Pages CHAPTER 6 INDUSTRY ANALYSIS PESTEL Analysis Economic †¢ Target market economic condition. †¢ Increasing production of low-quality products and imitations through cheap labor in other countries (ex. China). †¢ Poverty level is dominating the country’s population. 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Essay Topics on the Reformation - an in Depth Anaylsis on What Works and What Doesnt

Essay Topics on the Reformation - an in Depth Anaylsis on What Works and What Doesn't The Essay Topics on the Reformation Trap One of the absolute most important effects was exploration. There were different reformations which were caused due to the protestant reformation for instance, the counter reformation. The attacks on the monasteries aren't thought of as a reformation novelty. Creators of AI systems frequently have grand aspirations, and a few make grand claims. The Nuiances of Essay Topics on the Reformation The play also presents His human suffering a critical portion of the Christian faith poignantly, particularly in the song Gethsemane. Forget what you are aware of the church. Reformed worship wasn't such a lousy idea as Geneva originally thought. The aim of the Strasbourg Psalter was going to introduce a new sort of worship congregations haven't really had in quite a while. I really like the radical Catholic Church. The Council of Trent marked the start of the Counter Reformation. Luther was going to develop into a theologian. During the Reformation people like Martin Luther challenged the practices of such a highly effective institution like the church to produce changes. It's obvious there are no limits to the information that may be made available, provided that it can be geographically or spatially positioned on a map. In document E it demonstrates that the printing press helped to spread the very first map to record the presence of the American continents. We don't need to understand an excessive amount of background details. Real-time info or context sensitive info, can be put over physical map layers. Free Counter Reformation essay samples can be found FreeEssayHelp with no payment or registration. Still, every one of them would show up in the overall list. Appropriate template is completely used. Faith-based religion needs to be wrong. Luther believed that mankind is completely lost. This opposition from Luther can be associated with the period of renaissance particularly humanism. As an example, Calvin believed in the notion of predestination. Argument is orderly, but might have a couple inconsistencies. Religious beliefs seem to present such comforting certainty. As Christians consider the morality of AI, we have to reflect on the surveillance that enables machines to learn. Because Christians of all types already encounter AI daily, all of us have a responsibility to consider through its function in our lives. The Tried and True Method for Essay Topics on the Reformation in Step by Step Detail Just don't forget that appreciating its message isn't enough. No doubt it's a motivator today. Frequently used in reference to biblical matters, an exhortation can be reached about whatever you're passionate about and need to encourage other people to feel strongly about too. There's not anything wrong with that approach. I listened, attempting to demonstrate empathy, but I was confused because I didn't have any idea what she was referring to. Yet, there may be people who were thinking something similar. If someone were to try it, there would most probably be many men and women who'd oppose it. Essay Topics on the Reformation Help! The ideal was similar to the present notion of interdisciplinary studies where the student attempts to avert the hazards of overspecialization that may bring about an educational imbalance. To compose a strong exhortation, you have to appeal to the demands and desires of the reader. It's not merely a religious choice. Initially the motion proved to be a self-generated one. The main aim of the play is didactic. I want to stress that you may not win an argument against a position without initially considering it's truthfulness. Another of import component. If you don't understand where you're coming from, it's tricky to comprehend where you may be going. Actually, both translations came upon the world at almost the very same time because of the conditions of the day. Thus, a period of martyrdom came at the exact same moment. The early modern period proved to be a confusing moment. Martin believed he could change something. One wonders what Calvin thought of all this. Nevertheless, it's excellent to take note your Muslim colleagues may well be fasting. Frederick Douglass, considered Lincoln his pal and a buddy to black folks.

The Charismatic Leadership Style free essay sample

The Charismatic Leadership Style I have chosen to write my journal article on a leadership style known as a Ccharismatic Leader. Its difficult to identify the characteristics that make a leader charismatic, but they certainly include the ability to communicate on a very powerful emotional level, and probably include some personality traits. I do not believe that charismatic leadership is essential to be an effective leader but it can enhance the leadership journey. The Charismatic Leader gathers followers through based upon their personality and charm, rather than any form of external power or authority. Possessing these characteristics can be an extremely powerful way to gain and lead others. They can also make their followers (ordinary people) do some pretty extraordinary things. Charismatic leaders have the ability to sense the gap that exists between what an organization and culture of people and empower them to come together as one. By bridging this gap the leader can create a vision of a future state that everyone believes will be better than the current one. We will write a custom essay sample on The Charismatic Leadership Style or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page The charismatic leader often communicates their vision using metaphors and stories in ways that everyone can understand the vision. Their followers see the leader as one that possesses the ability to visualize the future with clarity. Their followers are also able to see how they fit into this future state and believe it will be better than today. Charismatic leaders do these things constantly in large and small ways. Charismatic Leaders are visionaries. They focus on transforming situations, not just maintaining. They will show great confidence in their followers. They are very persuasive and make very effective use of body language as well as verbal language. Many politicians use a charismatic style, as they need to gather a large number of followers. The person who I think is a great charismatic leader is Barack Obama. I have listened to a lot of his speeches and he has the power to motivate and empower people with his words, his testimony and his story of overcoming many trials and obstacles. Barack Obama is often compared to John F. Kennedy, who is arguably the most charismatic President of the United States. â€Å"Todays environment emphasizes organizational learning and follower empowerment conditions that promote mutual respect and dialogue. However, even in this environment leaders can, sometimes unwittingly, enact subtle abuses. Generally included in the typical definition of power are the notions of dependency and control: a leaders ability to determine followers behavior stems at least in part from the followers dependency on the leader. This, in turn, is based on leaders control over the various aspects of organizational life affecting followers or perceived as needed by followers, such as material resources and organizational advancement.

The Civil Rights Movement in the USA

Independent Schools in England essays

Independent Schools in England essays Great Britain has very diversified and complex school system, which has been undergoing frequent changes and reforms. However, there are still many controversies concerning the structure of the education system, one of them being organization and availability of independent schools. There are 2,400 schools in the UK which are not subject to local or central government control. They are sometimes called fee-paying (or, more accurately, fee-charging) schools because they charge parents fees and receive no state support. Nevertheless, there is no commonly agreed definition of the term. The core of independent sector is formed by several hundred public schools, which despite the name are not part of the state education system. Originally public meant that school offered free education to the public and was under public management, as opposed to private schools that were run for the benefit of their proprietor. Some of them date back to Middle Ages: Winchester was founded in 1394 and Eton in 1400. But the majority was established during the 19th century, since when the term public school has been applied to grammar schools that began charging some pupils fees, while the others were paid for from public funds. Today, independent schools throughout the country offer a wide choice of day and boarding schools, single-sex and coeducational ones, none of which has to follow National Curriculum. Instead, they offer a wider range of academic subjects, Classical Latin and Greek often being included. Which doesnt mean babies are tough these as it is possible to send a child of 2 to independent nursery. There are 4 types of independent schools: Nursery/Kindergarten mentioned above, for children aged 2 to 4 years; Pre-Preparatory for 3 or 4 to 7-year-olds; Preparatory accepting 7 to 11-year-olds; and finally Senior, arousing the most controversies but in the same time the most desirable, for teenagers aged 11 to 18. There are many...

Special Event Master Plan Assignment Example | Topics and Well Written Essays - 3250 words

Special Event Master Plan - Assignment Example There are a lot of topics that pertain to events, and more emphasis is targeted at sports teams and their venues in the tourism industry (Getz, 2012, p.5). According to John Tribe, tourism is a field of study, rather than a discipline that draws on a number of different individual disciplines. The essay is an illustration of a special event involving a 3k walk for humans, and a swimming event right after the event. We will seek permission from the Street Events Closure Permit to hold the 3K walk run for humans at least 180 days before the event as required by the Ordinance Chapter 14-8. Also, we will require the Sound Amplification Permit or Outdoor Music Venue Permit since we aim at playing music at the central and starting point of the race. Lastly, we will also be required to seek for the Private Security licenses for the entity performing private security personnel expected to safeguard the event. Start from Columbus Park and run through the city streets. The major landmark cities to be followed will be decided upon effectively by the management team. The proposed route for the 3K walks will be differentiated according to the different groups of participants. The route will be decided upon after through consultation with the city council to determine the best paths for the 3K walks. Participants will be notified as early as possible on the routes decided upon through fliers, mails and even traditional mails delivered to their homes. Upon receipt, we will host a training and familiarization workshop to provide appropriate guidelines on the exact path to be followed. Participants will be required to familiarize with the route several days before the event. Access to the full path will be denied two days prior to the event to safeguard the course and ensure the participants are safe on the actual day of the event. All the necessary measures pertaining to safety of the course wil l be put in place as required. Specific rules and regulations to be followed

Critique assignment Essay Example | Topics and Well Written Essays - 2000 words

Critique assignment - Essay Example It should be noted that the author has also helped in identifying a flow of the problem with the research purpose. The manner in which the topic has been discussed in the introduction makes it easier for the reader to expect the research methodology and findings. From the first instance of having a look at the title of the article, the readers can expect that the introduction will be able to create a textual as well as contextual construct. In simpler words, it can be said that the introduction of the article is clearly relevant with the objective as appointed by the author. It can also be said that the author has address some of the information tags in the introduction which may provide information which takes the reader beyond the understanding of article’s subject matter. This may be considered as irrelevant by some of the critiques but it is important to note that additional information in the introduction allows the readers to evaluate the peculiarities of the research. T hus, overall it can be said that the introduction written by the author in the article proves to be a stronger context to the research’s findings (Barton et al. 2012) The article has been published by International Journal of Audiology which is one of the most significant contributions in the field. The article was received on 15th September 2010. As per the reliability test, the acceptance of the article was done on 10 September 2011. Since the journal in publishing the content for the research purpose, it took another year for the journal to publish the article. The affiliation of the article is with International Journal of Audiology which makes it joint with British Society of Audiology and Nordic Audiological Society. The article’s publishing source, International Journal of Audiology has been a publishing source for many high-rated contributors in the field of audiology. The journal includes both original articles as well as reviews of

Haemoglobin-related Diseases Management Strategies

Haemoglobin-related Diseases Management Strategies Abstract Haemoglobinopathies or inherited disorders of haemoglobin are the most common monogenic disorders in humans. Red cell transfusion is a well accepted therapy for clinical management of the most severe form of haemoglobinopathies namely, sickle cell disease (SCD) and ÃŽ ²-thalassaemia major. Patients affected by SCD need red blood cell transfusions on a regular basis to reduce morbidity and mortality. The transfusions are administered intermittently to control or prevent a serious complication of SCD, and as a perioperative measure. Or, as a chronic procedure, transfusion strategy is applied to prevent the recurrence, or the first occurrence, of stroke which is a major crisis in SCD, and to manage pulmonary hypertension and other sources of morbidity and mortality. Exchange transfusions are used to reduce the sickle cell haemoglobin (HbS) levels during crisis. Several situations also exist wherein the indication for red cell transfusion is controversial, uncertain, or downright injudic ious. Many side effects of transfusion have been identified and methods to overcome them have been developed. Iron overload (remedy: iron chelation), and alloimmunisation (remedy: phenotypical matching of transfused blood) are two notable examples. Association of haemoglobinopathies and neurologic sequelae after transfusion is also known. At the present time, bone marrow transplant is the only curative procedure available for both SCD and ÃŽ ²-thalassaemia major. Potential therapies involving stem cell transplantation and gene techniques are being vigorously researched. A detailed discussion of the current status of clinical management strategies as applied to inherited haemoglobin-related diseases in particular, sickle cell disease and the thalassaemias, is presented in this paper. 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‚  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‚  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 (G TG). 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‚  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‚  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‚  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‚  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‚  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. (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‚  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 haematopoietic cells, and can result in macrocytic anaemia. 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 ACD (Krantz, 1994). Common childhood normocytic anaemias are, besides iron deficiency anaemia, those due to acute bleeding, sickle cell anaemia, 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 haemolytic normocytic anemias in children (Weat herall DJ, 1997a).   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 anaemia and increase together in macrocytic, hyperchromic anemia.   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 erythrocytes, due to bleeding or haemolysis. The reticulocyte count is typically higher.   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 (HbS) in which valine is substituted for glutamic acid at the sixth amino acid position in the beta globin gene reduces the solubility of haemoglobin, 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‚  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 tract generally indicative of malignancy (Hershko and Skikne, 2009).   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 del ivers 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‚  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 characteristically impaired in A CD, 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 cytokines causing impai rment of erythroid progenitor growth and haemoglobin production in developing erythrocytes.     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‚  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‚  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 mono cytes 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 disease including a critical 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). 4.1 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). 4.2 Red blood cell transfusion 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. 4.3 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). 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. ACS 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 recommended 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‚  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‚  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‚  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). 4.4 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). 4.5 Controversial and indeterminate indications for transfusion Several situations also exist wherein the indication for red cell transfusion is controversial, uncertain, or downright injudicious in SCD management. Some examples are indicated in Table 1.   Ã‚  Ã‚  Ã‚  Ã‚  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 therapy currently is only a second-line therapy in the management of priapism ( Miller et al., 1995).   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 (Febrile Non-Haemolytic Transfusion Reaction i.e., fever resulting from a blood transfusion) and alloimmunisation to HLAs (Human Leucocyte Antigens),   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 (E Haemoglobin-related Diseases Management Strategies Haemoglobin-related Diseases Management Strategies Abstract Haemoglobinopathies or inherited disorders of haemoglobin are the most common monogenic disorders in humans. Red cell transfusion is a well accepted therapy for clinical management of the most severe form of haemoglobinopathies namely, sickle cell disease (SCD) and ÃŽ ²-thalassaemia major. Patients affected by SCD need red blood cell transfusions on a regular basis to reduce morbidity and mortality. The transfusions are administered intermittently to control or prevent a serious complication of SCD, and as a perioperative measure. Or, as a chronic procedure, transfusion strategy is applied to prevent the recurrence, or the first occurrence, of stroke which is a major crisis in SCD, and to manage pulmonary hypertension and other sources of morbidity and mortality. Exchange transfusions are used to reduce the sickle cell haemoglobin (HbS) levels during crisis. Several situations also exist wherein the indication for red cell transfusion is controversial, uncertain, or downright injudic ious. Many side effects of transfusion have been identified and methods to overcome them have been developed. Iron overload (remedy: iron chelation), and alloimmunisation (remedy: phenotypical matching of transfused blood) are two notable examples. Association of haemoglobinopathies and neurologic sequelae after transfusion is also known. At the present time, bone marrow transplant is the only curative procedure available for both SCD and ÃŽ ²-thalassaemia major. Potential therapies involving stem cell transplantation and gene techniques are being vigorously researched. A detailed discussion of the current status of clinical management strategies as applied to inherited haemoglobin-related diseases in particular, sickle cell disease and the thalassaemias, is presented in this paper. 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‚  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‚  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 (G TG). 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‚  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‚  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‚  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‚  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‚  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. (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‚  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 haematopoietic cells, and can result in macrocytic anaemia. 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 ACD (Krantz, 1994). Common childhood normocytic anaemias are, besides iron deficiency anaemia, those due to acute bleeding, sickle cell anaemia, 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 haemolytic normocytic anemias in children (Weat herall DJ, 1997a).   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 anaemia and increase together in macrocytic, hyperchromic anemia.   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 erythrocytes, due to bleeding or haemolysis. The reticulocyte count is typically higher.   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 (HbS) in which valine is substituted for glutamic acid at the sixth amino acid position in the beta globin gene reduces the solubility of haemoglobin, 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‚  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 tract generally indicative of malignancy (Hershko and Skikne, 2009).   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 del ivers 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‚  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 characteristically impaired in A CD, 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 cytokines causing impai rment of erythroid progenitor growth and haemoglobin production in developing erythrocytes.     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‚  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‚  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 mono cytes 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 disease including a critical 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). 4.1 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). 4.2 Red blood cell transfusion 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. 4.3 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). 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. ACS 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 recommended 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‚  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‚  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‚  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). 4.4 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). 4.5 Controversial and indeterminate indications for transfusion Several situations also exist wherein the indication for red cell transfusion is controversial, uncertain, or downright injudicious in SCD management. Some examples are indicated in Table 1.   Ã‚  Ã‚  Ã‚  Ã‚  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 therapy currently is only a second-line therapy in the management of priapism ( Miller et al., 1995).   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 (Febrile Non-Haemolytic Transfusion Reaction i.e., fever resulting from a blood transfusion) and alloimmunisation to HLAs (Human Leucocyte Antigens),   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 (E