Thursday, November 28, 2019

Smoking Bans in US

Smoking is a widespread habit that causes many diseases. The issue of whether to ban smoking indoors by the governments of various countries is popular as they try to take a step towards curbing the harmful effects of smoking. People support smoking bans because they understand the harmful effects.Advertising We will write a custom research paper sample on Smoking Bans in US specifically for you for only $16.05 $11/page Learn More Some governments have put in place partial smoking bans, and others have passed total smoking bans. This literature review will focus on the whether the United States government should pass a nationwide indoor smoking ban. The difference between partial and total smoking bans. Moreover, smoking at workplaces. Wye, Bowman, Wiggers, Baker, Knight, Carr, et al (2010) says in Australia smoking is the leading cause of disease burden. The rate of smoking is very high among patients diagnosed with psychiatric disorders, and many of th em succumb to smoking related illnesses than their counterparts without the disorders. Total smoking ban is better than partial smoking ban because it protects non smokers from the effects of secondary smoke. The smokers find that they have to cut down the number of cigarettes they smoke in a day as long as they are in total ban smoking areas. The total smoking ban may encourage them to give up the habit. Whereas, partial smoking ban may paint the picture that smoking is fine as long as one does so in a designated area. Yet, the harmful effects continue to undermine their health. For instance, in a mental health facility that practices total smoking ban treatments for nicotine dependence are high unlike in those that have partial bans. For total smoking ban to be successful all the stakeholders in a health institution or in a country need to be included in the strategy. The inclusion of people in implementing the total smoking ban will lead to acceptance and compliance. If the stake holders are not included some will be hostile to the smoking ban, and it might not be successful. However, there is limitation in findings of prior researches on staffs’ view on the issue of total smoking bans in mental health institutions.Advertising Looking for research paper on social sciences? Let's see if we can help you! Get your first paper with 15% OFF Learn More The attitude towards smoking in the workplace is mainly negative (Walsh Paul, Paras, Stacey, Tzelepis, et al, 2011). Studies show that many people prefer if employees did not smoke at their workplaces. Many workplaces have implemented a total smoking ban. Many employees are okay with the ban because they do not like their smoking colleagues exposing them to secondary smoke. Moreover, employees waste time during working hours as they take a break to go. and smoke. The breaks affect their productivity hence they do not give their best to their employers. Thus, there is a negative attitude towards workers smoking in their work places. Therefore, one will not see many people smoking at the workplaces openly because of the negative attitude, but will see them smoking outside for instance in parks, bus or rail stops, and home. On the other hand, we have the partial smoking bans. Some governments have passed partial smoking bans to cut down on the cost of smoking both in social, and health terms. The introduction of the bans is not old and many countries such as the United States have taken a step to look into the effects of secondary smoke to people. The Center for Disease Control and Prevention was given the responsibility of studying the effects of secondhand smoke. The findings showed that the number of people suffering from heart attacks decreased. However, there is still no concrete evidence to support that short time exposure to secondary smoke leads to an increase in suffering from cardiovascular diseases. Secondhand smoke has been shown to cause problems to individuals a round the smoker and hence partial bans do not protect the people in the same environment as the smoker. For instance, some hotels and bars have smoking areas, but people near those areas are still exposed to the harmful effects of the secondary smoke. Some studies have been done to examine if partial smoking bans are effective than total smoking bans, and the pros and cons of each (Hofmann Nell, 2012). However, there is no conclusive study about which type of ban is better, but the bottom line is that smoking bans improve the welfare of the society.Advertising We will write a custom research paper sample on Smoking Bans in US specifically for you for only $16.05 $11/page Learn More In conclusion, the United States government should pass a nationwide indoors smoking ban because the harmful effects of smoking cannot be underestimated. The number of people suffering from smoke related diseases is high thus an indoor smoking ban can help to reduce the num bers. Moreover, many people seem to be in agreement that smoking indoors, and exposing the other people to secondary smoke is not good. Hence many would support the indoors smoking ban. The government needs to make a concerted effort to enforce laws against indoor smoking to protect its citizens from the negative effects of smoking, and ease the burden on the health sector. More importantly, the government should bring all the stakeholders on board so that they can support the indoor smoking ban, and avoid law suits by those who feel that the ban may be infringing on their personal freedoms. Besides, the population should be sensitized about the harmful effects of firsthand and secondhand smoke so that they can embrace the smoking bans and in the process deter those who are considering taking up the habit, and encourage those who smoke to quit. Reference List Hofmann, A., Nell, M. (2012). Smoking bans and the secondhand smoking problem: An economic analysis. The European Journal Of Health  Economics, 13(3), 227-236. doi:10.1007/s10198-011-0341-z Walsh, R., Paul, C., Paras, L., Stacey, F., Tzelepis, F. (2011). Workplace- related smoking in New South Wales: extent of bans, public attitudes and relationships with relapse. Health Promotion Journal of Australia, 22(2), 85- 90. Wye, P., Bowman, J., Wiggers, J., Baker, A., Knight, J., Carr, V., †¦ Clancy, R. (2010). Total smoking bans in psychiatric inpatient services: a survey of perceived benefits, barriers and support among staff. BMC Public Health,  10372-382. doi: 10.1186/1471-2458-10-372Advertising Looking for research paper on social sciences? Let's see if we can help you! Get your first paper with 15% OFF Learn More This research paper on Smoking Bans in US was written and submitted by user Fant0mex to help you with your own studies. You are free to use it for research and reference purposes in order to write your own paper; however, you must cite it accordingly. You can donate your paper here.

Sunday, November 24, 2019

“Houzit” Marketing management plan Essay Essays

â€Å"Houzit† Marketing management plan Essay Essays â€Å"Houzit† Marketing management plan Essay Paper â€Å"Houzit† Marketing management plan Essay Paper Marketing aims The market for home-wares in Brisbane is estimated last twelvemonth at $ 175 million per annum with an awaited growing rate of the per centum in the approaching twelvemonth. Here I outline the undermentioned selling aims: 12 % market portion ( up from 11 % ) Addition in gross revenues by 8. 5 % over last year’s consequence No enlargement shops are planned during this stage of consolidation and on mean the shops achieved $ 24. 680 per hebdomad for the twelvemonth. Selling activities Here we present the selling activities that show possible for the organization’s growing in seasonal demand that occurs during this period. Increased selling – focal point on magazine advertisement and PR In-store promotions– in-store shows will have advertisement visuals and ink the featured merchandises with other countries in Houzit’s mixture. Web based promotions- the company’s web page will besides transport the advertisement visuals on the place page and will utilize the PR transcript in article selling on popular article content sites. The web page will be targeted towards the key words found in the PR article and featured in the advertisement of ‘stylish bathroom’ and ‘exotic mirrors’ . These keywords will besides be secured via pay-per-click traffic directing. Focus in bathroom adjustments and mirror classs with linkages to the other two classs of sleeping room adjustments and cosmetic points. Key driver in accomplishing the selling aims is through the chance of holding publicizing infinite together with a PR write up in one of the taking home-ware magazines and their web site. For the following six months the selling program calls for increased selling to fit the growing in seasonal demand that occurs during this period. Integration of organisational activities Ad visuals and links will be displayed throughout at Houzit’s mixture and web home page. Company Web reference line of ‘Find us at hypertext transfer protocol: //www. houzit. com’ will be displayed on all stuffs. PR copy- used in article selling on popular article content sites. The web page will betargeted towards the Key word throughout. These keywords will besides be secured via pay-per-click traffic directing. Distribution and pricing Online retailing a new distributional channel- Company have decided to update the web page so that the clients can order and pay online. The Monetary value of imports will be monitored against rivals and exchange rate on day-to-day footing because imports were normally an country of high borders for the company and any loss there could be a serious issue. KPIs Market portion = shop sales/total estimated market gross revenuesMarketing cost of clients acquisition = cost of marketing / Total new concern acquired Delegation of functions and dutiesSelling director – enjoy taking duty for the in-store publicities because it keeps me connected with cardinal forces and tendency in ware class gross revenues. Tony – he is a specialist hunt engine optimizer and web page interior decorator Marie – advertisement /PR Lamberts confer withing – market research and selling auditsCommunication SchemesSelling communications is a instead generic term for a really of import map of selling. Communicating and circulating information has become progressively of import. While public dealingss are a signifier of selling communications. the function encompasses much more. including content development. merchandise placement and trade name messaging. Thus we will utilize the below methods to pass on efficaciously: 1. Shared electronic mails2. Formal meetings3. Informal meetings4. Team visits – shops5. Progress chart Assessment Task 2 – Case survey analysisStaffing support programSchemes: 1. Puting ends Will organize hebdomadal meeting by supplying to employees where can accomplish greatest return that to work toward and has the possible to increase productiveness in the workplace. 2. Supplying Feedback We believe that consistent feedback from wise mans and managers non merely helps better employee public presentation. but it ensures employees are non caught off guard when disciplined for hapless public presentation. 3. Celebrations and Wagess Celebrations and wagess will construct regard for the wise man or manager and assist employees see that the person is non merely at that place to knock but besides to portion in employee success. 4. Collaboration Directors will supply for new employees to join forces with as they begin working with a Houzit. I believe that directors help employees larn to voyage an organisation and how to finish undertakings efficaciously. Resources Marketing outcome theoretical account: ROI – Return on investing FeedbackSupplying the feedback utilizing the Star theoretical account:An easy manner to retrieve the elements of effectual feedback is to utilize the acronym STAR. ST – Situation or Task. What was the job. chance. challenge or undertaking? A – Action. What was said or done to manage the state of affairs or undertaking? Remember to supply developmental feedback and countries for betterment. R – Result. What was the impact of the employee’s attempts. and how did their actions influence the terminal consequence? Here’s an illustration of utilizing the STAR theoretical account to supply positive feedback. ST – â€Å"Thanks for finishing the spreadsheet on resource allotment I requested. † A – â€Å"You provided all of the information I asked for and got it to me on clip. † R – â€Å"I was able to convey the information to a planning meeting with our manager. where we used it to make a strong resource program for following term. † Scenario 1One-on-one coaching will includeRole-play activitiesTesting and reexamining repliesMeetings to promote the employee to execute and homework in which replies are reviewed The director provides the individualised coaching to her employee. May set up a clip line with preset intervals to reexamine advancement Scenario 2Performance measuring and Corrective actions such as:Ask the employee to rate themselvesSupply a written public presentation reappraisal to the employeeMake sure that can endorse up any positives and negatives with specific illustrations Conduct a reappraisal meeting within 48 hours of the written public presentation reappraisal Note and file any employee remarks and so guarantee that the concluding version goes on file. Custom-make the one-on-one coaching templet of Houzit company’s demands and manus to employees to finish prior to a public presentation reappraisal. Identifying failings: To measure our employees’ weaknesses we will see factors such as:TardinessCommunication jobsLack of enthusiasm or thrustPoor comprehension of stuffs or planTrouble acquiring along with others. We will work with each employee to come up with mensurable ends for betterment. For illustration: invent a system to track each employee’s advancement and cheque in on a regular basis. If an employee has a job with attending or tardiness. for case. make an attending chart and offer positive support. such as congratulations or acknowledgment for good attending each hebdomad. For employees with proficient jobs or a deficiency of apprehension. offer preparation on computing machine plans or systems. Other ways to track employees’ advancement may include holding employees maintain path of their day-to-day or hebdomadal gross revenues Numberss. For more subjective countries. such as people accomplishments. see keeping office seminars on subjects such as diverseness. via media or communicating or paying for employees to go to preparation. Offer inducements for the preparation - such as tiffin for all participants or a certification. Assessment Task 3 – Marketing public presentation studyMarketing aimsThe estimation for home-wares is presently $ 199 mln p. a up from $ 175 mln This year’s predicted growing 10 % and anticipating to go on for the following 5 old ages Average hebdomadal sale has grown $ 28. 200 although outlook was 8. 5 % growing on $ 24. 680 Market portion targeted 12 % Last 6 months marketing outgo:Advertising- $ 250. 000PR- $ 30. 000In shop promotion- $ 60. 000Internet marketing- $ 100. 000 The cause of the net income addition was we have successfully implemented the new schemes by actively prosecuting to accomplish the selling aims. There was a seasonal demand that occurred during the last twelvemonth by giving growing in portion from10-12 % . Increase in portion will be remained in following force able 5 old ages. which is giving more chance to Houzit stay in the market specifically continue to concentrating on magazine advertisement and PR. together with in shop publicities. Besides. we should put more on web based publicities in the following selling period. With a turning market we should keep the market portion to convey to the Houzit solid and governable growing. Targets We should keep our high public presentation every bit much as we can. There will be a big turning addition in interstate migration accordingly the home-wares and the edifice activity for at least following five old ages. Mentions 1. Joshi. Rakesh Mohan. ( 2005 ) International Marketing. Oxford University Press. New Delhi and New York 2. Philip Kotler. Philip. ; Kevin Lane Keller ( 2006 ) . Marketing Management. 12th erectile dysfunction. : ) . Pearson Prentice Hall 3. Clancy. Kevin J. ; Peter C. Kriegafsd ( 2000 ) . Counter intuitive Marketing. The Free Press 4. Porter. Michael ( 1998 ) . Competitive Strategy ( revised ed. ) . The Free Press. 5. Kotler. Philip. ; Kevin Lane Keller ( 2006 ) . Marketing Management. 12th erectile dysfunction. Pearson Prentice Hall 6. Ries. Al ; Jack Trout ( 2000 ) . Positioning: The Battle for Your Mind ( twentieth day of remembrance ed. ) 7. Porter. Michael ( 1998 ) . Competitive Advantage ( revised ed. ) . The Free Imperativeness

Thursday, November 21, 2019

Cross Cultural Communication Essay Example | Topics and Well Written Essays - 2250 words

Cross Cultural Communication - Essay Example Part 1 International Journal of Cross Cultural Management (IJCCM) In managing of the global conflict resolution, attention should be given to cross cultural factors. Whereas the value of culture in managerial behavior has long been acknowledged, intellects of political science are still coming to terms with the perception and its repercussions. Conventional approaches to disagreement stress the dominance of the state while overlooking several the distinctive internal features, which vary between nations. Foulkes & Bercovitch view culture indeed has a weighty outcome on how nations view the world, conduct themselves in it, and handle their conflicts. Culture has become crucial in the existing environment, where largely conflict occurs frequently between factions, alienated along cultural lines, within a nation. Evaluation of the relevance of ideas, and cultural differences does undeniably have a substantial impact on arbitration and conflict resolution. The journal also elaborates the effects of effective communication and motivation in a cross-cultural environment. European Journal of Cross-Cultural Competence and Management (EJCCM) This journal explains the extensive field of cross-cultural examination with an allusion to an organization in practice. The chief purpose is the establishment of a podium for the debate on cultural matters in current industry across several disciplines and cultures. In the spirit of its founding organization, EJCCM influences contributions from dissimilar fields of science involved in the interrelations and relations amid culture. The journal encourages papers about the dynamics of cross-cultural interactions in Europe. Key challenges Building of trust between employees and management of an organization is very important. Group members should be capable to rely on each other’s words and work as a team. Trust is a considerable challenge in cross-cultural groups, as people only tend to trust those from their nations and the sa me culture (Thomas, & Thomas, 2008, 134). Trust building is beneficial if the team leader and team members working together at a similar location for a long time, despite diverse nationalities (Steers, Sa?nchez-R, & Nardon, 2010, 213). Managing of people from different nationalities has different convictions and perceptions. This diversity makes it a challenge to manage them especially when a conflict occurs. Bosses need to apply different leadership styles in dealing with conflict (Velo, 2012, 40). Managing of language and cultural issues is another challenge. In any conflict resolution, communication is inevitable. In managing of a cross-cultural conflict, where different people speak various languages, it is essential for individuals to appreciate one another (Velo, 2012, 40). Synchronizing the languages and cultural aspects to enable people have a common ground remains a challenge (Thomas, & Thomas, 2008, 134). As a team leader, working with members from different cultures has b een a vast experience. Every step in the team was a learning experience. The group taught us that diversity is strength. The tasks assigned to us went well as we were able to respect each other’s opinions to find a common ground. We remained objective during the entire session focusing on the group’s mandate and not personal mandate. From a management point of view, we learnt tolerance, empathy and respect. Since we are from different backgrounds, there was a need for

Wednesday, November 20, 2019

Wheelchair regulation Coursework Example | Topics and Well Written Essays - 500 words

Wheelchair regulation - Coursework Example The manual wheelchairs rely on the attendant so that the can move and they do not use electricity. The other two classes are powered by electricity. Class two of invalid carriages consist of mobility scooters and powered wheelchairs that are designed to be used on pavements with a maximum speed limit of 6 km/h (8 mph). Class three powered wheelchairs and mobility scooters of invalid have a maximum speed limit of (12 km/h) and their purpose is for the use of road only. It is important to note that they are also equipped with a facility designed to travel on pavement or footpath at a speed of 6 km/h (4 mph). The law  states that theClass three vehicles may only be used by a disabled person who is aged 14 years and above. The other two classes, Class one and Class 2, however, may be used by a non-disabled person who is demonstrating the vehicle for sale or a disabled person. Clause 37 states that when the vehicle users is have a duty to adhere to the direction or rules of other vehicl es when they are on operation on the road. It also adds that the vehicle users on the pavements should follow the guidance and rule of the pedestrians. The second section concentrates of the usage of mobility scooters and powered wheelchairs on the pavements (38 to 40). Clause 38 explains how vehicle users should treat the other pavement users and pedestrians and especially those that have a visual or hearing impairment. It insists on the use of pavements rather than roads for safety purposes of the vehicle users. In a nut-sell, the rule aims at protecting both the users and non-users of the vehicles. Clause 39 points out the need for users of powered vehicles and scooters to use speeds not exceeding four mph (6 km/h) on footpaths and pedestrian areas. It also highlights that the user may be required to adjust to the other pavement users in case the path is not wide enough or if the pavement

Sunday, November 17, 2019

Compare and contrast how two named health care systems deal with one Essay

Compare and contrast how two named health care systems deal with one specific health issue - Essay Example The society-associated MRSA (CA-MRSA), frequently starts as a painful skin boil. Thereafter, it spreads through skin-to-skin contact (Ayliffe & English, 2003). Groups such as child care workers, people living in congested and contaminated places as well as conditions high school are prone to this infection. It is relatively difficult to treat MRSA infections than most strains of staphylococcus Aureus due to its resistance to some of the antibiotics that are commonly used. The resistance of antibiotics can happen in several ways. Strains of bacteria can mutate and over a long period develops resistance to a certain antibiotic (Bischofberger,  2011). Similarly, if one is treated with an antibiotic, there is a high chance that it will destroy many of the undamaging strains of bacteria that live on and in the body. Thus, allowing resistant bacteria to multiply rapidly and take their place in the body. Recently, the overuse of antibiotic is the primary reason why there is resistance of antibiotic and superbugs (Weigelt,  2008). Others factors are; not completing recommended doses of antibiotics and also using antibiotics to treat minor situations that could have been well without using such them. The concern about the effects of hospital-acquired infections has a significant European dimension. It has been projected that 8 to 12% of the patients admitted to hospitals within the European states suffer from severe infections while receiving medication (McCartney & Health Protection Agency, 2009). The European Center for Disease Prevention and Control (ECDC) stated that about 4.1 million patients in EU are affected (European Commission, 2009). According to ECDC, this infection result to the deaths of 37,000 people per year. Another concern is the use of multi-drug resistant bacteria in various health care institutions. The possibility of developing MRSA in a care homes or hospitals

Friday, November 15, 2019

Causes, Symptoms and Treatments of Anaemia

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

Tuesday, November 12, 2019

Lady Macbeth, Macbeths One-of-a-Kind Woman Essay -- Macbeth essays

Macbeth's One-of-a-Kind Woman      Ã‚  Ã‚   Shakespeare's Macbeth portrays the indomitable, manipulative character of Lady Macbeth through bold, sinister actions. Her character will be the subject of this essay.    Lily B. Campbell in her volume of criticism, Shakespeare's Tragic Heroes: Slaves of Passion, examines the effect of sin on the life of the first lady:    Act v presents swiftly and relentlessly the results of passion, of the passion which has become mortal sin. First it is Lady Macbeth that we see enduring the fate of the sinful in whom fear and remorse have already begun to effect the punishment for evil. That Shakespeare chose to manifest Lady Macbeth's melancholy as a disturbance in her sleep shows that he was a student of the moral philosophy of the time, for as we have seen earlier, all the accounts of fear are concerned with the effect of fear on sleep. (232)    In Shakespeare and Tragedy John Bayley interprets Lady Macbeth's character through her speech:    'The milk of human kindness' and the 'illness' that should attend ambition are cruder concepts, in Lady Macbeth's mouth, than they now seem to be. She is not saying her husband is too kind a man for this business, and with too healthy a spirit; 'kindness' means human nature, and Macbeth's is not mature or manly, has not learnt the necessary hardness of the world. Her husband is in a sense her child, fed with the milk which is natural to her, and when the word recurs in the Senecan speech which follows, she calls on the spirits that tend on mortal thoughts, schemes of murder, to turn her milk to gall. She will feed him on that to produce an appropriate response, as the armed men in the tale sprang from the sowing of dragon's teeth... ...Blakemore Evans. Boston: Houghton Mifflin Company, 1972.    Knights, L.C. "Macbeth." Shakespeare: The Tragedies. A Collectiion of Critical Essays. Alfred Harbage, ed. Englewwod Cliffs, NJ: Prentice-Hall, Inc., 1964.    Mack, Maynard. Everybody's Shakespeare: Reflections Chiefly on the Tragedies. Lincoln, NB: University of Nebraska Press, 1993.    Shakespeare, William. The Tragedy of Macbeth. http://chemicool.com/Shakespeare/macbeth/full.html, no lin.    Siddons, Sarah. "Memoranda: Remarks on the Character of Lady Macbeth." The Life of Mrs. Siddons. Thomas Campbell. London: Effingham Wilson, 1834. Rpt. in Women Reading Shakespeare 1660-1900. Ann Thompson and Sasha Roberts, eds. Manchester, UK: Manchester University Press, 1997.    Wilson, H. S. On the Design of Shakespearean Tragedy. Toronto, Canada: University of Toronto Press, 1957.

Sunday, November 10, 2019

Review the Laws Related to Security and Privacy of Data Essay

Computer Misuse Act 1990  This act was introduced to prevent users hacking. This also stops them entering a computer, programs or files without authorisation, this act is in place to prevent users to use the internet without permission to cause an act of crime and also prevents unauthorised modifications to a computer. This act does not allow any attacks on a server as this is illegal. Hacking into a computer is not allowed as it can disrupt the business as personal information can be stolen and also be used in crime, this can cause a problem in the businesses finance sector. Anyone who knowingly hacks into a computer with intent to steal information is going against this act. Anyone who misuses the computer in this way is going against the law as they are using it for criminal acts. This act also does not allow anyone to use a fraudulent credit card or any other card to make a purchase via the internet. Hackers who overload networks with data to intently disable them can face a prison sentence for up to 10 years. This act makes it illegal for users to upload pornography of someone and children as people will find the offensive, having possession or viewing these types of materials could get the user in to trouble by the law. Users must not use the computer to harass or stalk a particular person, it is also the same when making telephone conversations as the user can not use offensive or threatening language they can face a sixth month imprisonment. This allows the organisation to take action and take back whats rightfully there and also punish the hacker as they are covered by this law, this bring a sense of security as this law ould put the hackers from obtaining information wrongly. Copyright Designs and Patents Act 1988 This is the current UK copyright law which has been created since 1988, it gives artist and creators of, musical and dramatic or any other artist have the right to control their work, this allows them to have control over how their material is used, this right covers broadcast and public performance, copying, adapting, issuing, renting and lending copies to the public. It is not what has been created it’s the details within what has been created to be protected, for example if you have a idea for a book that would not be protected however the information and content within the book that is written will be protected. So someone else can write a book around your idea but they cannot copy your book or adapt your book to do so. This helps to protect security and privacy of data as it protects the effort money and time someone has put in to create their content, if this content is being copied the organisation will lose potential customers as someone is using their content to sell another product. Privacy and compensation requirements of Data Protection Act 1984 1998 2000 This legislation first was written in 1984 there are updated version of this data protection act and the one that is used and most updated is the 2000 version, the 1998 version was a broadened and replaced the data protection act 1984, the main purpose for this law is that it gives rights and privacy of individuals, this ensure that their data is not processed without the creators knowledge and is only process with the consent of the artist. This act covers personal data relating to living individuals and protects sensitive personal data of that individual. This act covers data held in electronic formats. This has been changed as over time new technology and items are able to store data this is now updated so that it can cover these items as they will contain sensitive and personal data to an individual. The 2000 version of this act contains added laws and have been updated. This protects the security of the individual as no one should be allowed to take private and sensitive data without the individual being aware of this. Copyrights This exclusive legal right that is given to the original artist to print, perform film, publish or record literary and authorize others to do so for heir material. This protects a physical expression of ideas , for example someone has an idea to write a book the content that is written in that book is covered by the copyright act as it will be unique to the creator. You do not need to register or claim copyright, this protection is automatic as soon as it is created. If someone steals information or wrongly sells other work or creation for their own financial benefit then this copy right act will protect the original creator and he can claim back the money that has been gained by the person who has taken the material without permission. This protects security and the use of private data as it does not allow anyone to take data or material without the author permission, if this does happen the user who has taken this material can be fined and prosecuted as the products does not belong to them, the author can also decide how his material has been used and if someone breaks his restriction they can also be prosecuted. Open Source  This is software or material that is available with the source, this allows users to copy the material and modify the material, the reason for this is because the creators would believe that if someone can edit the material for themselves it will be more useful to another persona and will also allow less problems to occur if the source is available, so organisation believe that it should not be given and source should not be shown, they usually give the compiled version this is so others cannot copy their material and modify this. Open source means that it is available to any one and they can modify it however they want, doing this will improve the security for a material such as software as this source code has been given to the users it will be less likely that someone would want to hack it and modify the code as it is already available. This does have some restrictions as it would like to preserve the name and authors of the material. Freeware  This is software that is offered free of charge and is downloadable off the internet, freeware is different to shareware as shareware would require payment. Even though freeware is available it does have a license this would have restriction as some freeware would not want the user to alter the program, repackage it or sell the freeware, redistribution is allowed of freeware but cannot be distributed for money purposes. The creators want to ive something to the community but want to retain control of any future development of the software, this allows users to have the material without making changes and is free to the users, this makes there coding private and cannot be used however as it is free hackers would not bother to steal or resell this type of material as anyone can get it online for free, this makes the software more secure as there is no risk as it does not hold any value. Shareware  This usually is software that is distributed, this allows users to use the product and then pay for the product after the trial version has finished, you can then only continue to use the full version if you feel like the product is good to use but will have to pay to get the full version, the user will then be covered for registration and then support for the software if they purchase, once purchased additional features are usually given as only who pay can have these. This is been protected under copyright, even though you are able to use this software without payment you are still restricted to what you are allowed to do with it which is selling this software or adding it to another. This allows users to use expensive and powerful software for free and a short period of time however will later need to pay as the trial reaches to its end. This relates to security and privacy as the creators do not mind users having a full version for a short period as they may see as an advantage to sell their product later, copyright protects shareware as users cannot manipulate or sell their product. Commercial Software This is a software that is designed for sale to meet a commercial need for a user, this type of software is only allowed to be used for commercial purposes, this is software that you would usually see in the retailers in a physical box and requires payment before it can be used, commercial software usually contain a registration key and when you purchase this you will acquire a licence to use it. You are still able to download commercial software and this can be often seen in sharewares. These are usually made available directly from the organisation website. This relates to security and privacy of data as the user has to purchase the software before they can use it as they will not receive a registration key not allowing them to use the software, this does make it a security risk as hackers will try to steal a registration key but the copyright act protects the organisation and can prosecute the hacker for stealing data from the organisation.