PhD Dissertation Chapter 1

The Fundamental ComponentsChapter One, one of any research thesis or dissertation, should lay down the basis and the objectives any researcher would want to achieve in such undertaking.This chapter consists of the background and Theoretical Framework of the Study, Statement of the Problem and the Hypotheses, Significance of the Study, the Definition of Terms and Delimitation. The statements made in these subsections should be clearly stated.  In the first subsection, the background will formally introduce the topic and discuss the rationale of choosing the problem as well as its theoretical framework.  Another one is that the Statement of the Problem and the Hypotheses should be couched in clear and measurable terms. This part describes the purposes why the researcher is conducting the study and enumerates the hypotheses to be tested.Third, the Significance of the Study will cite the benefits that could be derived as a result.  Next, the definition of terms should give the conc eptual as well as the operational meanings of the terms in relation to the present study.  Finally, the Delimitation part will set the limits and scope of the Study.The AnalysisThe subject of the present analysis is the Chapter of a Dissertation Proposal.The Background of the StudyAs stated previously in the explanation of the Background of the Study, the Chapter 1 of the present research lacks a Research Title to serve as a basis of the Chapter 1 component of the dissertation. Having no title, the researcher or the reader of the present work will have a hard time guessing what the Chapter was all about. Thus, he will only have to guess the appropriate title of this research which is missing. The research describes the different â€Å"excellent models† used by other developed countries. Since this is the case, these models to my mind bear no relevance to what the research is all about neither to be used as a link to the research title.Though I must admit that the researcher stated his intention or reason for conducting these research â€Å"is to provide theoretical background to the ‘claim’ that the TPEM is strongly based on management theory† this thus not negate the fact that in using to explain his intention through â€Å"TQM and performance-based models, Resource-based View (RBV) and the stakeholder theory (ST)† he employed a research paradigm which was not properly explained either in in-text or via graphical representation. How can the researchers establish a prior relationship â€Å"between enablers and performance indicators is important before testing their causal linkages?† It should be properly explained.The Problem Statement and Research ObjectivesThe Statement of the Problem section provides a description of the purpose of the study and enumerates the Hypotheses to be tested.  The researcher in this part stated the the enabler consist of leadership, organizational culture and values, strategies and obje ctives, best practices, innovation, and change management; and the results set comprises of productivity, employee satisfaction, customer relationship and stakeholder focus and the performance results. To my mind these are the variables that will be used to attain the researcher’s desired end.The Statement of the Problem here is couched in general terms which is very difficult to determine what statistical tool to be used or is it measurable using statistics. To wit: [h]ow similar is TPEM to other previous performance models such as MBNQA, EQA and Kanji’s. What similarities or differences that co-exist between TQM based models such as MBNQA, EQA or Kanji’s and other performance-based models such as Competitive fitness model, Blue-chip characteristics, and World class manufacturing model; {s]ince TPEM is claimed to be beyond quality management perspectives, does the model have strong foundation in management theories.   What theories could explain its performan ce factors or enablers and what are the theoretical roots of model’s performance factors; and [d]o the dimensions identified as enablers (called capabilities, and stakeholder focus in this thesis) affect company performance.This statement should be reduced into simple terms that could be measured, even in practical terms, by a given statistical tools; otherwise, it will be very hard to come up with a concrete answer for these statements.  Ã‚  In like manner, some of the objectives or the specific questions that need to be answered are couched in general terms or even misplaced, to wit:   Ã¢â‚¬Å"[t]theoretically clarify the TPEM within management theories; to clarify each enablers (organizational capability and stakeholder focus) as determined by TQM and other related performance-based models; to clarify the company performance dimension of the result portion of total performance model; to establish a suitable measurement items for each dimension of capability, stakeholder focus and company performance; to validate the dimensions of the model; to test the relationship between each dimension of the capability, stakeholder focus against company performance; to test the structural linkage between organizational capability, stakeholder focus, and company performance with the stakeholder focus as a mediating variable; and to test the goodness of fit of the model.†How can we measure through clarification the company performance dimension of the result portion of total performance model? How can we establish in a statistical terms a suitable measurement items for each dimension of capability, stakeholder focus and company performance? How can we validate the model’s dimension? How can we measure the structural linkage between organizational capability, stakeholder focus, and company performance with the stakeholder focus as a mediating variable? To me this is quite broad and diffused.In the question â€Å"to test the relationship between each dimension of the capability, stakeholder focus against company performance† this should be stated in this manner: Is there a relationship between†¦Ã¢â‚¬ ¦..stakeholders focus and company performance? Lastly, never state in the object the kind of statistical tool to be used as in this case â€Å"to test the goodness of fit of the model.† Use the word â€Å"association or relationship† in forming the specific objectives.  In general, the objective part needs to be re-written in order to respond to the Problem Statement. Otherwise, the aims of the research will not be attained.Significance of the StudyIn this section, the researcher should focus on the study’s significance to its purported end user. Never explain literature or describe the models. Stay on the unique significance of the present study to the community or organization where the researcher belongs.Definition of TermsThe definition of term lacks the conceptual and operational definition of terms of selected words unique to the study. The researcher only includes a purported definition without even citing the correct reference of each term of words. Also, the researcher failed to include the operational definition of this words as used in the thesis or dissertation.ReferenceShearer, C (1994). Practical Continuous Improvement for Professional Services, ASQC  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Quality Press, Milwaukee, Wisconsin, p. 163-165.

Kingdom Protista

Kingdom Protista: Characteristics Mostly unicellular, eukaryotic cells Reproduce asexually or sexually by conjugation Exhibit all three modes of nutrition Photosynthesis Ingestion Absorption Ultimately spawned all multicellular kingdoms Very diverse kingdom Difficult for taxonomists to agree on classification Diverse Modes of Nutrition Use diverse modes of nutrition Ingest food Absorb nutrients from surroundings Photosynthesis Protists that ingest food are typically predators Use extensions of cell membrane called psuedopods to surround and engulf prey item Diverse Modes of NutritionProtists that absorb nutrients directly from the surrounding environment can be Free-living types in the soil that decompose organic dead matter Parasites that live inside the bodies of other organisms, sometimes harming the host Diverse Modes of Nutrition Some protists have photosynthetic organelles called chloroplasts Photosynthetic protists are abundant in oceans, lakes, and ponds Free floating Mutuall y beneficial associations with other organisms: solar energy captured by the protist is used by host, which shelters and protects the protist Diverse Modes of NutritionPhotosynthetic protists are collectively known as algae Single-celled, non-photosynthetic protists are collectively known as protozoa Diverse Modes of Reproduction Most protists reproduce asexually by mitotic cell division Some also reproduce sexually Two individuals contribute genetic material to an offspring that is genetically different from either parent Occurs during certain time of year or circumstances (e. g. a crowded environment or a food shortage) Protist Reproduction Asexual Sexual (a) (b) Effects on HumansPositive impact – ecological role of photosynthetic marine protists (algae) capture solar energy and make it available to the other organisms in the ecosystem release oxygen gas Negative impact – many human and plant diseases are caused by parasitic protists Major Groups of Protists Protist classification is in transition Genetic comparison reveals evolutionary history of organisms Genetic, instead of physical features now separate protist species into different lineages Some physically dissimilar species are now placed in a common lineage The Excovates Lack mitochondriaTwo major groups Diplomonads: have two nuclei and move about by means of multiple flagella Parabasalids: live inside animals Parabasalids Mutually beneficial relationships with other species Parabasalid inhabits gut of termite Termite delivers food to parabasalid, which digests and releases nutrients to termite Parabasalids Harms host species Trichomonas vaginalis causes the sexually transmitted disease trichomoniasis Trichomonas inhabits urinary and reproductive tracts, using flagella to move through them Causes vaginal itching and discharge in females The EuglenozoansHave distinctive mitochondria Two major groups Euglenids Kinetoplastids Euglenids Single-celled, fresh-water protists Lack a rigid outer covering Best known example is Euglena Moves by whipping single flagellum Photosynthetic Some euglenids photosynthetic, others absorb/engulf food Euglenids Photoreceptor (eyespot) found in some euglenoids Provides for a way to sense location of light source Useful for photosynthetic euglenoids in maximizing photosynthesis Euglena : a Representative Euglenoid Flagellum Eye Spot Contractile Vacuole Stored Food Nucleus Nucleolus Chloroplasts KinetoplastidsAll species have one or more flagella Can be used for propulsion, sensing, or food gathering Many are free-living in soil and water Kinetoplastids Some species live in a symbiotic mutualistic association within another organism Some species digest cellulose in termite guts Trypanosomes live within tsetse flies and cause African sleeping sickness in fly-bitten mammals Trypanosomes infect the blood causing African sleeping sickness Trypanosomes in Blood The Stramenophiles Have fine, hair-like projections on flagella Mostly single-celle d but some multicellularSome are photosynthetic species Major stramenophile groups Water molds Diatoms Brown algae Water Molds Also known as oomycetes Long filaments aggregated into cottony tufts Many are soil and water-based decomposers Water Molds Profound economic impacts caused by water molds Late blight attacks potato plants (caused Irish potato famine in 1845) One species causes downy mildew (nearly destroyed French wine industry in 1870s) A Parasitic Water Mold Downy mildew on grapes Diatoms Found in both fresh and salt water Photosynthetic Produce shells of silica that fit togetherDiatomaceous earth is deposits of diatom shells (mined and used as an abrasive) Diatoms Part of floating phytoplankton community Important in absorbing CO 2 and producing O 2 Phytoplankton perform 70% of all photosynthesis Diatoms are important as food in marine food webs Herbivorous organisms â€Å"graze† on these â€Å"pastures of the sea† Brown Algae Form multicellular aggregates ( seaweeds) Superficially similar but not closely related to plants Contain brownish-yellow and green (chlorophyll) pigments producing brown/olive appearance Brown Algae Nearly all marineFound along rocky shores of temperature oceans Includes giant kelp Several species use gas-filled floats to support body Giant kelp forests provide food and shelter for sea animals Diverse Brown Algae Fucus sp. Giant Kelp The Alveolates Single-celled protists with small cavities beneath cell surface (alveoli) Comprise a distinct lineage Nutritional modes include photosynthetic, parasitic, and predatory The Alveolates Major alveolate groups Dinoflagellates Apicomplexans Ciliates Dinoflagellates Mostly photosynthetic Two whip-like flagellaMost species live in salt water Some species bioluminescent Certain specialized dinoflagellates live within coral, clam, and other protistan hosts Cell wall resembles armored plates Dinoflagellates & Red Tide Red Tide Dinoflagellates Nutrient-rich water causes populati on explosion called â€Å"red tides† Substantial fish kills result from oxygen depletion and clogged gills Oysters, mussels, and clams benefit from large food supply but may accumulate nerve poison Lethal paralytic shellfish poisoning in humans may result from eating these shellfishApicomplexans Also known as sporozoans All members are parasitic Form infectious spores Spores transmitted between hosts by food, water, or insect bites Apicomplexans Complex life cycle (e. g. Plasmodium- malarial parasite) Parasite passed to human by Anopheles mosquito Plasmodium develops in liver, makes spores in red blood cells (causing fever upon release) New mosquitoes acquire parasite while feeding on blood Plasmodium quickly evolves resistance to drugs Ciliates Inhabits both fresh and salt waterHighly complex unicellular organization Specialized organelles Cilia that propel cells through water at 1 mm/s Ciliates Examples of ciliate complexity Paramecium (contractile vacuoles, nervous system) Didinium (predator of other microbes) Paramecium has vacuoles and cilia The Complexity of Ciliates Macronucleus Micronucleus Food Vacuole Oral Groove Contractile Vacuole Cilia Food Vacuole forming The Cercozoans Cercozoans have thin, threadlike psuedopods, which extend through hard shells in some species Cercozoans includeForaminifera Radiolarians The Cercozoans Foraminiferans produce elaborate calcium carbonate shells with holes Deposits of fossilized foraminiferans form chalk Radiolarians have silica shells Heliozoans The Amoebozoans Amoebozoans move by extending finger-shaped pseudopods, also used for feeding Inhabit aquatic and terrestrial environments Generally do not have shells The major groups of amoebozoans are Amoebas Slime molds The Amoebozoans Amoebas Found in freshwater lakes and ponds Predators that stalk and engulf preyOne species causes amoebic dysentery The Amoebas The Slime Molds Distinctly unique lineage among protists Physical form blurs distinction between a co lony versus an individual The Slime Molds Two-phase life cycle Mobile feeding stage Stationary, reproductive stage forming a fruiting body Two main types Acellular Cellular Acellular Slime Molds Also known as plasmodial slime molds Composed of a thinly spread cytoplasm with multiple diploid nuclei Plasmodial mass feeds on bacteria and organic matter by engulfing them Acellular Slime MoldsCan form bright yellow or orange masses Dry conditions or starvation stimulate fruiting body formation Haploid spores produced Spores disperse and germinate into a new plasmodium The Acellular Slime Mold Physarum (a) (b) Cellular Slime Molds Live in soil as independent haploid cells Pseudopodia surround and engulf food (like bacteria) Cellular Slime Molds Food scarcity creates a pseudoplasmodium Individual cells release chemical signal if food is scarce Dense, slug-like aggregation of cells forms Slug† crawls towards light, forms a fruiting body Haploid spores produced are dispersed to form ne w single-celled individuals The Life Cycle of a Cellular Slime Mold Single, amoeba-like cells emerge from spores, crawl, and feed. When food is scarce, cells aggregate into slug-like mass called pseudoplasmodium. Pseudoplasmodium migrates toward light, forms fruiting bodies; produces spores. fruiting bodies spores nucleus The Red Algae Multicellular, photosynthetic seaweeds Pigments combined with chlorophyll produce bright red to black appearances Found exclusively in marine environmentsThe Red Algae Very common in deep, clear tropical waters Red pigments absorb deeply penetrating blue-green light Can therefore live deeper than other seaweeds The Red Algae Diversity of forms and uses Some species deposit calcium carbonate Some species harvested for food Energy captured by red algae important in food chains Products extracted from red algae include: Carrageenan (stabilizing agent) Agar (substrate for bacteria in petri dishes) The Red Algae Multicellular, photosynthetic seaweeds, rang ing in color from bright red to nearly black Live in clear tropical oceansSome species deposit calcium carbonate, which contributes to the formation of reefs Red Algae The Green Algae All species photosynthetic Both multicellular and unicellular species Found in both freshwater and marine environments Some form long filamentous chains of cells (e. g. Spirogyra ) Spirogyra: A Green Algae The Green Algae Some form colonies of clustered cells (e. g. Volvox ) Mostly microscopic forms but Ulva (sea lettuce) is a multicellular leaf-sized green algal seaweed The Green Algae Green algae are closely related to plantsThe earliest plants may have been similar to today’s multicellular green algae Protists and Life Marine phytoplankton: 70% of all photosynthesis Diatoms – abrasive products and oil reserves Sarcodines and limestone deposits Protists and disease Water molds – downy mildew, late blight of potato Dinoflagellates and â€Å"red tide,† shellfish poisoning Zo oflagellates – African sleeping sickness, Giardia Sarcodines – amoebic dysentery Sporozoans – Plasmodium and malaria Giardia: the Curse of Campers

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Critically analyse the approach to Knowledge Management at Tata Steel Essay

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Should the Oxford's word of the year to be included in a formal Research Paper

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The Ottoman Empire Paper Essay Example for Free

The Ottoman Empire Paper Essay The Ottoman Empire was one of the ancient yet one of the most powerful and influential world empires.   The history of this empire begins sometimes during the 13th century.   In their bid to enlarge their territory they took no consideration to any limits or boundaries be it religious, tribal or otherwise.   This empire is also viewed as one of the civilized empires of the modern times. The empire was more of a military administration than a state.   The empire is considered to have lasted a considerably longer time than any other empire.    The rulers of this empire were known as Sultans or Hunkar or Emperors and were all Islam.   Suleyman the Great was the Sultan who ruled the longest while Amurath ruled for only three months making him the shortest ruling sultan.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   The sultans always emerged from the Ottoman family who were strict followers of the Quran.   Honesty, hard work and charity were principles that led the Ottoman Empire.   Sermons were always read in the name of the reigning Sultan at that time.   Any property belonging to the Sultan was known as Royal or imperial.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Having discussed that much on the establishment and general history of the Ottoman of the empire, it is of utmost importance to now look at the empire more critically and find out impacts of the Ottoman Empire especially on the Umma Muslims.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Though the Ottoman Empire was one of the most powerful and civilized ancient empires of the world, it also had its weak points during its reign.   This paper specifically focuses on some of those weak points and particularly the mismanagement that was witnessed when the empire was in power leading to division among the Umma Muslims.   A critical analysis of the Ottoman Empire reveals various setbacks that the dynasty experienced and this affected directly or indirectly the unity of the Ottoman Muslims. According to the traditions of the Ottoman Empire, when a Sultan died one of his sons would become the next Sultan.   However there were no proper strategies as to who would become the next Sultan. There was therefore no clear criterion of selecting a Sultan. This led to bloodshed as the one who eventually emerged victorious had to eliminate his rivals for order and calmness to prevail.   This obviously went against the teachings of the Muslim religion.   Some Muslims supported the method while others were totally opposed to it as it contravened the teachings of the Holy Quran.   This led to division among the Muslims.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Another issue that led to the division of the Umma Muslims was the level of respect accorded to the sultans.   The Sultans were almost equated to Allah the God of the Muslims.   For instance during prayers sermons were read in the name of the current Sultan.   Some Muslims however felt that this was blasphemous because ordinarily sermons were supposed to be read in the name of Allah the Mighty one.   This therefore led to division among Muslims thereby breaking the unity between them.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   As discussed earlier Sultan Suleyman served for 40 years and therefore goes down the history of books as the longest serving Sultan.  Ã‚   The major role of the Sultan was to ensure that justice and fairness was exercised.   Cases of injustice were rare as the Sultan made sure that the laws were followed to the letter.   Any injustice and unfairness called for the direct intervention of the Sultan. Scholars and theologians believe that one of the reasons why the Ottoman dynasty declined and eventually collapsed was because the Sultans who succeeded Sultan Suleyman were not keen on protecting the interests of the citizens in terms of justice.   The neglect by their leaders led to Umma Muslims to lack loyalty for their leaders and thereby there was disunity among them.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   When Sultan died his son Selim II took over the leadership of the dynasty. His behavior was absolutely intolerable and contributed a great deal in causing disunity among the Muslims.   He was an addict of alcohol and would spend most of his days drinking therefore forgetting his administrative role.   He was also a lover of women and a sex addict vices that are heavily condemned in the Holy Quran.   Due to his negligent nature, he completely disengaged himself from making decisions that affected the common people directly or indirectly.   This made the Muslims to be disloyal to the Sultan and thereby led to a lot of division. As a consequence the Ottoman dynasty came tumbling down marking the end of the great dynasty. (Paul, 1971)   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   At the end of the sixteen century Ottoman was still a very strong dynasty and influential too.   However the Sultan style of leadership was slowly becoming unpopular thus losing ground.   In its place was the bureaucratic power method of ruling.   However this method of power was actually the pathway to the decline and collapse of the world’s most influential empire.  Ã‚   This was so because bureaucracy led to corruption neglecting the needs and interests of the people.   As a result, there was a lot of unpopularity of the government among the common people.   This led to division among the Muslims and eventually the dynasty collapsed. (Leslie, 2003)   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Historians also believe that another major contribution to disunity among the Ottoman Muslims was inequality by successors of Sultan Suleiyman.   As discussed earlier during the reign of Sultan Suleiyman the Central government was accessible so that any person who had grievances would present them before the leaders.   However with the change of leaders, the new leaders ranked themselves so highly that they were not accessible.   The Muslims lost faith in their leaders; consequently there was disunity and eventual collapse of the dynasty. The leaders promoted people to power without using the right criteria.   There was gross unfairness and this brought about strife among the common people.   This in turn led to divisions among the Muslims as some felt that they were discriminated against in their own country.   At some point the leaders exuded high level of negligence as far as matters pertaining people were concerned.   The common people revolted and as a result there was disunity.   This led to internal attacks.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Another major issue that brought about division due to poor management of power by the leaders was the issue of succession upon the death of a Sultan.   As already discussed if the deceased Sultan was without an heir or that he had several sons there was stiff contest that always led to bloodshed.   Scholars strongly believe that this may have played a major role in division of the Umma and the eventual collapse of the kingdom.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   A notable distinction between the Ottoman Empire and other empires was that they were during the Ottoman Empire there was freedom especially for the non-Muslims to practice their own religion.   This brought division among the Muslims as some felt that other religions were equated to their religion and this they found to be very offensive.   As a result there were massacres and discrimination.  Ã‚   This led to a great division among the Muslims most of whom felt that though no religion should be equated with the Muslim religion Massacre was a sin as it contravened the Holy Quran.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   There was also an element of divide and rule that leaders in power used in attempt to gain popularity.   The leaders would therefore incite the people against their own.   The people fought each other over small disputes but this was the plan of the leaders in order to rule them more easily.   This was a great power mismanagement that saw the Muslims divide into big factions depending on whose side they actually belonged. (Shaw, 1977)   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   There was great self-centeredness and selfishness among the leaders which again brought division.   This was especially so when it came to sharing of resources.   There was unfair sharing and distribution of resources that brought hatred and thus division among the Muslims.   The leaders only considered themselves and their families forgetting the rest of the people.   Some people felt sidelined and as a result there were factions and consequently these groupings led to division among the Umma Muslims.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Another challenge that the Ottoman Empire faced was classification of Muslims.   The Shia Muslims, the Umma and other classifications.   Every class felt that they dominated the rest.   This again brought about division because all classes of Muslims felt that they would want to be considered superior to the rest.   This eventually brought about division among the Muslims as no group agreed to be treated as lesser of the other.   The major division came about when some groups demanded that the rest of the groups must convert and become one of their own.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Division also arose when the dynasty made arrangements to fight other kingdoms.   The empire could not reach an agreement as to who would go to the war.   This again brought division because those not selected felt that they were not given an opportunity to fight for themselves thus there were differences on these grounds.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   There is also clear mismanagement of the empire by the leaders when they did not give ample protection to their own.   Most of the promises made by their leaders were never fulfilled or honored.   The leaders who took after Suleiman put their interests first and forgot the people.   The people were neglected and those who were treated well were just a small group.   This discrimination resulted to obvious indifferences thereby there was disunity among people who were once united.(Donald,2005) As discussed earlier, after the death of sultan Suleyman, so many things changed.   Corruption was very rampant especially when it came to provision of basic social amenities to the people.   Services that were normally offered free had to be paid for and as result there was agitation and revolt among the people leading to division.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   There was a gross alteration of rules, laws and policies that governed the people.   The leaders made alterations in their favor.   The common people were very disappointed and began to rebel.   The rebellions and revolts ended up in bringing divisions among the once united Umma Muslims community.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   The other major cause of rift was education in that there are those who were provided with good quality education while the rest could only access the traditional education.   This in turn was reflected in terms of development so that those with high quality education were seen to develop more than the rest.   This led to social classification and thereby division.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   From the various issues discussed it is very clear that decline and eventual collapse of the Ottoman kingdom was caused by issues affecting them internally and not attacks and conquest by Europe and other world powers.   It is the mismanagement by their leaders that led to the division of the Umma Muslims and finally the most powerful and influential dynasty in the ancient times collapsed. Works Cited Quartaert Donald. The Ottoman Empire. London, Cambridge University Press, 2005 Peirce Leslie. Law and Gender in the Ottoman Court, New York. University of California Press, 2003 Shaw Stanford. History of the Ottoman Empire. London, Cambridge University Press, 1977 Wittek Paul. Rise of the Ottoman Empire, Turkey, B. Franklin, 1971

Haemoglobin-related Diseases Management Strategies

Haemoglobin-related Diseases Management Strategies Abstract Haemoglobinopathies or inherited disorders of haemoglobin are the most common monogenic disorders in humans. Red cell transfusion is a well accepted therapy for clinical management of the most severe form of haemoglobinopathies namely, sickle cell disease (SCD) and ÃŽ ²-thalassaemia major. Patients affected by SCD need red blood cell transfusions on a regular basis to reduce morbidity and mortality. The transfusions are administered intermittently to control or prevent a serious complication of SCD, and as a perioperative measure. Or, as a chronic procedure, transfusion strategy is applied to prevent the recurrence, or the first occurrence, of stroke which is a major crisis in SCD, and to manage pulmonary hypertension and other sources of morbidity and mortality. Exchange transfusions are used to reduce the sickle cell haemoglobin (HbS) levels during crisis. Several situations also exist wherein the indication for red cell transfusion is controversial, uncertain, or downright injudic ious. Many side effects of transfusion have been identified and methods to overcome them have been developed. Iron overload (remedy: iron chelation), and alloimmunisation (remedy: phenotypical matching of transfused blood) are two notable examples. Association of haemoglobinopathies and neurologic sequelae after transfusion is also known. At the present time, bone marrow transplant is the only curative procedure available for both SCD and ÃŽ ²-thalassaemia major. Potential therapies involving stem cell transplantation and gene techniques are being vigorously researched. A detailed discussion of the current status of clinical management strategies as applied to inherited haemoglobin-related diseases in particular, sickle cell disease and the thalassaemias, is presented in this paper. 1. Introduction Anaemia is a syndrome characterised by a lack of healthy red blood cells or haemoglobin deficiency in the red blood cells, resulting in inadequate oxygen supply to the tissues. The condition can be temporary, long-term or chronic, and of mild to severe intensity. There are many forms and causes of anaemia. Normal blood consists of three types of blood cells: white blood cells (leucocytes), platelets and red blood cells (erythrocytes). The first generation of erythrocyte precursors in the developing foetus are produced in the yolk sac. They are carried to the developing liver by the blood where they form mature red blood cells that are required to meet the metabolic needs of the foetus. Until the 18th week of gestation, erythrocytes are produced only by liver after which the production shifts to the spleen and the bone marrow. The life of a red blood cell is about 127 days or 4 months (Shemin and Rittenberg, 1946; Kohgo et al., 2008). The main causes of anaemia are blood loss, product ion of too few red blood cells by the bone marrow or a rapid destruction of cells.   Ã‚  Ã‚  Ã‚  Ã‚  Haemoglobin, a protein, present in the red blood cells is involved in the transport of oxygen from the lungs to all the other organs and tissues of the body. Iron is an important constituent of the haemoglobin protein structure which is intimately involved in the transport of oxygen. Anaemia is generally defined as a lower than normal haemoglobin concentration. The normal blood haemoglobin concentration is dependent on age and sex, and, according to the World Health Organisation (WHO) Expert Committee Report, anaemia results when the blood concentration of haemoglobin falls below 130 g/L in men or 120 g/L in non-pregnant women (WHO, 1968). However, the reference range of haemoglobin concentration in blood could vary depending on the ethnicity, age, sex, environmental conditions and food habits of the population analysed. According to Beutler and Warren (2006), more reasonable benchmarks for anaemia are 137 g/L for white men aged between 20 and 60 years and 132 g/L for older men. The value for women of all ages would be 122 g/L. Also, the lower limit of normal of haemoglobin concentrations of African Americans are appreciably lower than that of Caucasians (Beutler and Warren, 2006).   Ã‚  Ã‚  Ã‚  Ã‚  Besides the well recognised iron deficiency anaemia, several inherited anaemias are also known. These are mostly haemoglobinopathies. Adult haemoglobin is a tetrameric haeme-protein. Abnormalities of beta-chain or alpha-chain produce the various medically significant haemoglobinopathies. The variations in amino acid composition induced genetically impart marked differences in the oxygen carrying properties of haemoglobin. Mutations in the haemoglobin genes cause disorders that are qualitative abnormalities in the synthesis of haemoglobin (e.g., sickle cell disease) and some that are quantitative abnormalities that pertain to the rate of haemoglobin synthesis (e.g., the thalassemias) (Weatherall., 1969). In SCD, the missense mutation in the ÃŽ ²-globin gene causes the disorder. The mutation causing sickle cell anemia is a single nucleotide substitution (A to T) in the codon for amino acid 6. The substitution converts a glutamic acid codon (GAG) to a valine codon (G TG). The form of haemoglobin in persons with sickle cell anemia is referred to as HbS. Also, the valine for glutamic acid replacement causes the haemoglobin tetramers to aggregate into arrays upon deoxygenation in the tissues. This aggregation leads to deformation of the red blood cell making it relatively inflexible and restrict its movement in the capillary beds. Repeated cycles of oxygenation and deoxygenation lead to irreversible sickling and clogging of the fine capillaries. Incessant clogging of the capillary beds damages the kidneys, heart and lungs while the constant destruction of the sickled red blood cells triggers chronic anaemia and episodes of hyperbilirubinaemia.   Ã‚  Ã‚  Ã‚  Ã‚  Fanconi anaemia (FA) is an autosomal recessive condition, and the most common type of inherited bone marrow failure syndrome. The clinical features of FA are haematological with aplastic anaemia, myelodysplastic syndrome (MDS), and acute myeloid leukaemia (AML) being increasingly present in homozygotes (Tischkowitz and Hodgson, 2003). Cooleys anaemia is yet another disorder caused by a defect in haemoglobin synthesis.   Ã‚  Ã‚  Ã‚  Ã‚  Autoimmune haemolytic anaemia is a syndrome in which individuals produce antibodies directed against one of their own erythrocyte membrane antigens. The condition results in diminished haemoglobin concentrations on account of shortened red blood cell lifespan (Sokol et al., 1992).   Ã‚  Ã‚  Ã‚  Ã‚  Megaloblastic anaemia is a blood disorder in which anaemia occurs with erythrocytes which are larger in size than normal. The disorder is usually associated with a deficiency of vitamin B12 or folic acid . It can also be caused by alcohol abuse, drugs that impact DNA such as anti-cancer drugs, leukaemia, and certain inherited disorders among others (Dugdale, 2008).   Ã‚  Ã‚  Ã‚  Ã‚  Malaria causes increased deformability of vivax-infected red blood cells (Anstey et al., 2009). Malarial anaemia occurs due to lysis of parasite-infected and non-parasitised erythroblasts as also by the effect of parasite products on erythropoiesis (Ru et al., 2009).   Ã‚  Ã‚  Ã‚  Ã‚  Large amounts of iron are needed for haemoglobin synthesis by erythroblasts in the bone marrow. Transferrin receptor 1 (TfR1) expressed highly in erythroblasts plays an important role in extracellular iron uptake (Kohgo et al., 2008). Inside the erythroblasts, iron transported into the mitochondria gets incorporated into the haeme ring in a multistep pathway. Genetic abnormalities in this pathway cause the phenotype of ringed sideroblastic anemias (Fleming, 2002). The sideroblastic anemias are a heterogeneous group of acquired and inherited bone marrow disorders, characterised by mitochondrial iron overload in developing red blood cells. These conditions are diagnosed by the presence of pathologic iron deposits in erythroblast mitochondria (Bottomley, 2006).   2. Classification of anaemia Anaemia can be generally classified based on the morphology of the red blood cells, the pathogenic spectra or clinical presentation (Chulilla et al., 2009). The morphological classification is based on mean corpuscular volume (MCV) and comprises of microcytic, macrocytic and normocytic anaemia. (a) Microcytic anaemia refers to the presence of RBCs smaller than normal volume, the reduced MCV ( 15 would probably indicate IDA (Chulilla et al., 2009).   Ã‚  Ã‚  Ã‚  Ã‚  In macrocytic anaemia, erythrocytes are larger (MCV > 98 fL) than their normal volume (MCV = 82-98 fL). Vitamin B12 deficiency leads to delayed DNA synthesis in rapidly growing haematopoietic cells, and can result in macrocytic anaemia. Drugs that interfere with nucleic acid metabolism, such as.hydroxyurea increases MCV (> 110 fL) while alcohol induces a moderate macrocytosis (100-110 fL). In the initial stage, most anaemias are normocytic. The causes of normocytic anaemia are nutritional deficiency, renal failure and haemolytic anemia (Tefferi, 2003). The most common normocytic anaemia in adults is ACD (Krantz, 1994). Common childhood normocytic anaemias are, besides iron deficiency anaemia, those due to acute bleeding, sickle cell anaemia, red blood cell membrane disorders and current or recent infections especially in the very young (Bessman et al., 1983). Homozygous sickle cell disease is the most common cause of haemolytic normocytic anemias in children (Weat herall DJ, 1997a).   Ã‚  Ã‚  Ã‚  Ã‚  In practice, the morphological classification is quicker and therefore, more useful as a diagnostic tool. Besides, MCV is also closely linked to mean corpuscular haemoglobin (MCH), which denotes mean haemoglobin per erythrocyte expressed in picograms (Chulilla et al., 2009). Thus, MCV and MCH decrease simultaneously in microcytic, hypochromic anaemia and increase together in macrocytic, hyperchromic anemia.   Ã‚  Ã‚  Ã‚  Ã‚  Pathogenic classification of anaemia is based on the production pattern of RBC: whether anaemia is due to inadequate production or loss of erythrocytes caused by bleeding or haemolysis. This approach is useful in those cases where MCV is normal. Pathogenic classification is also essential for proper recognition of the mechanisms involved in the genesis of anaemia. Based on the pathogenic mechanisms, anaemia is further divided into two types namely, (i) hypo-regenerative in which the bone marrow production of erythrocytes is decreased because of impaired function, decreased number of precursor cells, reduced bone marrow infiltration, or lack of nutrients; and (ii) regenerative: when bone marrow upregulates the production of erythrocytes in response to the low erythrocyte mass (Chulilla et al., 2009). This is typified by increased generation of erythropoietin in response to lowered haemoglobin concentration, and also reflects a loss of erythrocytes, due to bleeding or haemolysis. The reticulocyte count is typically higher.   Ã‚  Ã‚  Ã‚  Ã‚  Sickle cell disease is characterised by sickled red cells.   The first report of SCD was published a century ago noting the presence of peculiar elongated cells in blood by James Herrick, an American physician (1910). Pauling et al. (1949) described it as a molecular disease. The molecular nature of sickle haemoglobin (HbS) in which valine is substituted for glutamic acid at the sixth amino acid position in the beta globin gene reduces the solubility of haemoglobin, causing red cells to sickle (Fig. 1). Sickling of cells occurs at first reversibly, then finally as a state of permanent distortion, when cells containing HbS and inadequate amounts of other haemoglobins including foetal haemoglobin, which retards sickling, become deoxygenated (Bunn, 1997). The abnormal red cells break down, leading to anaemia, and clog blood vessels with aggregates, leading to recurrent episodes of severe pain and multiorgan ischaemic damage (Creary et al., 2007). The high levels of inflammatory cytokines in SCD may promote retention of iron by macrophage/reticuloendothelial cells and/or renal cells. SCD care commonly depends on transfusion that results in iron overload (Walter et al., 2009). 3. Pathogenesis of anaemia Anaemia is a symptom , or a syndrome, and not a disease (Chulilla et al., 2009). Several types of anaemia have been recognised, the pathogenesis of each being unique. Iron deficiency anaemia (IDA) is the most common type of anaemia due to nutritional causes encountered worldwide (Killip et al., 2008). Iron is one of the essential micronutrients required for normal erythropoietic function While the causes of iron deficiency vary significantly depending on chronological age and gender, IDA can reduce work capacity in adults (Haas Brownlie, 2001) and affect motor and mental development in children (Halterman et al., 2001). The metabolism of iron is uniquely controlled by absorption rather than excretion (Siah et al., 2006). Iron absorption typically occurring in the duodenum accounts for only 5 to 10 per cent of the amount ingested in homoeostatis. The value decreases further under conditions of iron overload, and increases up to fivefold under conditions of iron depletion (Killip et al., 2008). Iron is ingested as haem iron (10%) present in meat, and as non-haem ionic form iron (90%) found in plant and dairy products. In the absence of a regulated excretion of iron through the liver or kidneys, the only way iron is lost from the body is through bleeding and sloughing of cells. Thus, men and non-menstruating women lose about 1 mg of iron per day while menstruating women could normally lose up to 1.025 mg of iron per day (Killip et al., 2008). The requirements for erythropoiesis   which are typically 20-30 mg/day   are dependent on the internal turnover of iron (Munoz et al., 2009) For example, the amount of iron required for daily production of 300 billion RBCs (20-30 mg) is provided mostly by recycling iron by macrophages (Andrews, 1999).   Ã‚  Ã‚  Ã‚  Ã‚  Iron deficiency occurs when the metabolic demand for iron exceeds the amount available for absorption through consumption. Deficiency of nutritional intake of iron is important, while abnormal iron absorption due to hereditary or acquired iron-refractory iron deficiency anemia (IRIDA) is another important cause of unexplained iron deficiency. However, IDA is commonly attributed to blood loss e.g., physiological losses in women of reproductive age. It might also represent occult bleeding from the gastrointestinal tract generally indicative of malignancy (Hershko and Skikne, 2009).   Ã‚  Ã‚  Ã‚  Ã‚  Iron absorption and loss play an important role in the pathogenesis and management of IDA. Human iron disorders are necessarily disorders of iron balance or iron distribution. Iron homeostasis involves accurate control of intestinal iron absorption, efficient utilisation of iron for erythropoiesis, proper recycling of iron from senescent erythrocytes, and regulated storage of iron by hepatocytes and macrophages (Andrews, 2008). Iron deficiency is largely acquired, resulting from blood loss (e.g., from intestinal parasitosis), from inadequate dietary iron intake, or both. Infections, for example, with H pylori, can lead to profound iron deficiency anemia without significant bleeding. Genetic defects can cause iron deficiency anaemia. Mutations in the genes encoding DMT1 (SLC11A2) and glutaredoxin 5 (GLRX5) lead to autosomal recessive hypochromic, microcytic anaemia (Mims et al., 2005). Transferrin is a protein that keeps iron nonreactive in the circulation, and del ivers iron to cells possessing specific transferrin receptors such as TFR1 which is found in largest amounts on erythroid precursors. Mutations in the TF gene leading to deficiency of serum transferrin causes disruption in the transfer of iron to erythroid precursors thereby producing an enormous increase in intestinal iron absorption and consequent tissue iron deposition (Beutler et al., 2000). Quigley et al. (2004) found a haem exporter, FLVCR, which appears to be necessary for normal erythroid development. Inactivation of FLVCR gene after birth in mice led to severe macrocytic anaemia, indicating haem export to be important for normal erythropoiesis.   Ã‚  Ã‚  Ã‚  Ã‚  The anaemia of chronic disease (ACD) found in patients with chronic infectious, inflammatory, and neoplastic disorders is the second most frequently encountered anaemia after iron-deficiency anaemia. It is most often a normochromic, normocytic anaemia that is primarily caused by an inadequate production of red cells, with low reticulocyte production (Krantz, 1994). The pathogenesis of ACD is unequivocally linked to increased production of the cytokines including tumour necrosis factor, interleukin-1, and the interferons that mediate the immune or inflammatory response. The various processes leading to the development of ACD such as reduced life span of red cells, diminished erythropoietin effect on anaemia, insufficient erythroid colony formation in response to erythropoietin, and impaired bioavailability of reticuloendothelial iron stores appear to be caused by inflammatory cytokines (Means, 1996;2003). Although iron metabolism is characteristically impaired in A CD, it may not play a key role in the pathogenesis of ACD (Spivak, 2002). Neither is the lack of available iron central to the pathogenesis of the syndrome, according to Spivak (2002), who found reduced iron absorption and decreased erythroblast transferrin-receptor expression to be the result of impaired erythropoietin production and inhibition of its activity by cytokines. However, reduced erythropoietin activity, mostly from reduced production, plays a pivotal role in the pathogenesis of ACD observed in systemic autoimmune diseases (Bertero and Caligaris-Cappio, 1997). Indeed, iron metabolism as well as nitric oxide (NO), which contributes to the regulation of iron cellular metabolism are involved in the pathogenesis of ACD in systemic autoimmune disorders. Inflammatory mediators, particularly the cytokines, are important factors involved in the pathogenesis of the anaemia of chronic disease, as seen in rheumatoid arthritis anaemia (Baer et al., 1990), the cytokines causing impai rment of erythroid progenitor growth and haemoglobin production in developing erythrocytes.     Ã‚  Ã‚  Ã‚  Ã‚  Anaemia is also commonly found in cases of congestive heart failure (CHF), again caused by excessive cytokine production leading to reduced erythropoietin secretion, interference with erythropoietin activity in the bone marrow and reduced iron supply to the bone marrow (Silverberg et al., 2004). However, in the presence of chronic kidney insufficiency, abnormal erythropoietin production in the kidney plays a role in the pathogenesis of anaemia in CHF.   Ã‚  Ã‚  Ã‚  Ã‚  The myelodysplastic syndromes (MDS) are common haematological malignancies affecting mostly the elderly as age-related telomere shortening enhances genomic instability (Rosenfeld and List, 2000). Radiation, smoking and exposure to toxic compounds e.g., pesticides, organic chemicals and heavy metals, are factors promoting the onset of MDS via damage caused to progenitor cells, and, thereby, inducing immune suppression of progenitor cell growth and maturation. TNF- and other pro-apoptotic cytokines could play a central role in the impaired haematopoiesis of MDS (Rosenfeld and List, 2000). Premature intramedullary cell death brought about by excessive apoptosis is another important pathogenetic mechanism in MDS (Aul et al., 1998).     Ã‚  Ã‚  Ã‚  Ã‚  SCD arising from a point mutation in the ÃŽ ²-globin gene and leading to the expression of haemoglobin S (HbS) is the most common monogenetic disorder worldwide. Chronic intravascular haemolysis and anaemia are some important characteristics of SCD. Intravascular haemolysis causes endothelial dysfunction marked by reduced nitric oxide (NO) bioavailability and NO resistance, leading to acute vasoconstriction and, subsequently, pulmonary hypertension (Gladwin and Kato, 2005).    However, a feature that differentiates SCD from other chronic haemolytic syndromes is the persistent and intense inflammatory condition present in SCD. The primary pathogenetic event in SCD is the intracellular polymerisation or gelation of deoxygenated HbS leading to rigidity in erythrocytes (Wun, 2001). The deformation of erythrocytes containing HbS is dependent on the concentration of haemoglobin in the deoxy conformation (Rodgers et al., 1985). It has been demonstrated that sickle mono cytes are activated which, in turn, activate endothelial cells and cause vascular inflammation. The vaso-occlusive processes in SCD involve inflammatory and adhesion molecules such as the cell adhesion molecules (CAM family), which play a role in the firm adhesion of reticulocytes and leukocytes to endothelial cells, and the selectins, which play a role in leukocyte and platelet rolling on the vascular wall (Connes et al., 2008). Thus, inflammation, leucocyte adhesion to vascular endothelium, and subsequent endothelial injury are other crucial factors contributing to the pathogenesis of SCD (Jison et al., 2004). 4. Current therapies for clinical management of sickle cell disease including a critical appraisal of transfusion Between 1973 and 2003, the average life expectancy of a patient with SCD increased dramatically from a mere 14 years to 50 years thanks to the development of comprehensive care models and painstaking research efforts in both basic sciences especially molecular and genetic studies, and clinical aspects of SCD (Claster and Vichinsky, 2003). The clinical manifestations of SCD are highly variable. Both the phenotypic expression and intensity of the syndrome are vastly different among patients and also vary longitudinally within the same patient (Ballas, 1998). New pathophysiological insights available have enabled treatments to be developed for the recognised haematologic and nonhaematologic abnormalities in SCD (Claster and Vichinsky, 2003). The main goals of SCD treatment are symptom alleviation, crises avoidance and effective management of disease complications. The strategy adopted is primarily palliative in nature, and consists of supportive, symptomatic and preventative approaches to therapy. Symptomatic management includes pain mitigation, management of vasoocclusive crisis, improving chronic haemolytic anaemia, treatment of organ failure associated with the disease, and detection and treatment of pulmonary hypertension (Distenfeld and Woermann, 2009). The preventative strategies include use of prophylactic antibiotics (e.g., penicillin) in children, prophylactic blood transfusion for prevention of stroke in patients especially young children who are at a very high risk of stroke, and treatment with hydroxyurea of patients experiencing frequent acute painful episodes (Ballas, 2002). Currently, curative therapy for sickle cell anaemia is only available through bone marrow and stem cell transplantation. Hematopoietic cell transplantation using stem cells from a matched sibling donor has yielded excellent results in paediatric patients (Krishnamurti, 2007). Curative gene therapy is still at the exploratory stage (Ballas, 2002). 4.1 Current and potential therapies The potential treatment strategies basically target cellular dehydration, sickle haemoglobin concentrations, endothelial dysfunction, and abnormal coagulation regulation (Claster and Vichinsky, 2003). HbS concentrations are essentially tackled through transfusions while approaches to reduce HbS polymerisation which is the main mechanism for the development of vaso-occlusion include (a) increasing foetal haemoglobin (HbF) concentration using hydroxyurea (Fig. 2), butyrate, or erythropoietin, and (b) preventing sickle cell dehydration using Clotrimazole (Fig. 3) or Mg2+pidolate. Hydroxyurea therapy increases the production of HbF in patients with sickle cell anaemia, and, thereby, inhibits the polymerisation of HbS and alleviates both the haemolytic and vaso-occlusive manifestations of the disease (Goldberg et al., 1990). Recombinant erythropoietin also increases the number of reticulocytes with HbF. Additionally, it has been observed that administration of intravenous recombinant eryt hropoietin with iron supplementation alternating with hydroxyurea enhances HbF levels more than hydroxyurea alone (Rodgers et al., 1993). As SCD is essentially characterized by an abnormal state of endothelial cell activation   that is, a state of inflammation, a pharmacologic approach to inhibit endothelial cell activation has proved clinically beneficial (Hebbel and Vercellotti, 1997). Thus, administration of sulfasalazine which is a powerful inhibitor of activation of nuclear factor (NF)-B, the transcription factor promoting expression of genes for a number of pro-adhesive and procoagulant molecules on endothelium to humans has been found to provide transcriptional regulation of SCD at the endothelium level (Solovey et al., 2001). 4.2 Red blood cell transfusion A key therapy that is applied regularly in the clinical management of patients with SCD is packed red blood cell transfusion. RBC transfusion improves the oxygen-carrying capacity which is achieved by enhancing the haemoglobin levels, causes dilution of HbS concentration thereby, reducing blood viscosity and boosting oxygen saturation. Furthermore, RBC transfusion is helpful in suppressing endogenous production of sickle RBCs by augmenting tissue oxygenation ( Josephson et al., 2007). There are two major types of RBC transfusion therapy: intermittent and chronic which are further classified as prophylactic or therapeutic. Intermittent transfusions are generally therapeutic in nature and administered to control acute manifestations of SCD whereas chronic transfusions are performed as general preventative measures to check complications of SCD. RBC transfusion given as a single dose is termed as simple transfusion. Exchange transfusion involves administration of a larger volume of RBCs replacing the patients RBCs that are simultaneously removed. Details of the various types of RBC transfusion and the major clinical indications for the same in SCD patients are listed in Table 1. 4.3 Indications for intermittent transfusions Indications for intermittent transfusions include acute manifestations of SCD, as indicated in Table 1, that require redressal through therapeutic transfusions. However, under certain circumstances intermittent transfusions could be prophylactic such as for instance, when SCD patients are transfused before specific surgeries viz., those related to pregnancy complications or renal failure (Table 1). Acute Chest Syndrome (ACS) describes a manifestation of SCD in which, due to sickling, infectious and noninfectious pulmonary events are complicated, resulting in a more severe clinical course. The diagnosis is the presence of a new infiltrate on chest radiography that is accompanied by acute respiratory symptoms. ACS accounts for nearly 25% of all deaths from SCD (Vichinsky, 2002). Repeated episodes of ACS are associated with an increased risk of chronic lung disease and pulmonary hypertension (Castro, 1996). The severe pulmonary events occurring in SCD may be precipitated by any trigger of hypoxia (Vichinsky, 2002). Transfusions are very efficacious and provide immediate benefit by reversing hypoxia in ACS. Transfusion of leucocyte-poor packed red cells matched for Rh, C, E, and Kell antigens can curtail antibody formation to below 1% (Vichinsky, 2002). Simple transfusions suffice for less severe cases; however, exchange transfusion is recommended to minimise the risk of increased viscosity. Also, chronic transfusion appears promising for prevention of recurrence in selected patients (Styles and Vichinsky, 1994). In a multicentre ACS trial, prophylactic transfusion was found to almost completely eliminate the risk of pulmonary complications (Vichinsky, 2002).   Ã‚  Ã‚  Ã‚  Ã‚  Acute Symptomatic Anaemia arises in SCD as a result of blood loss, increased RBC destruction, suppression of erythropoiesis etc. and is effectively treated with intermittent transfusion of RBCs to relieve symptoms of cardiac and respiratory distress (Josephson et al., 2007).   Ã‚  Ã‚  Ã‚  Ã‚  Aplastic Anaemia is commonly caused in SCD on account of infection of haematopoietic precursors in the bone marrow by Parvovirus B19 leading to a steep fall in RBCs. According to Josephson et al. (2007), therapeutic intermittent transfusion of RBCs is again the recommended first-line of treatment to improve total haemoglobin count and prevent cardiac decompensation. However, in those patients who are prone to fluid overload on account of cardiac or renal dysfunction an alternative transfusion strategy is to remove the whole blood and replace it with packed cells while avoiding the addition of excess volume (Josephson et al., 2007).   Ã‚  Ã‚  Ã‚  Ã‚  Acute Stroke is a high risk especially in paediatric SCD cases because of elevated cerebral flow. Enormous decline in stroke rate have occurred in children receiving intermittent simple transfusion (Adams et al., 1998). However, the identification of the stroke type would be necessary in all SCD patients in order to determine the appropriate treatment approach since the occurrence of infarctive strokes is higher in children as opposed to a higher incidence of haemorrhagic strokes in adults (Adams, 2003). 4.4 Indications for Chronic Transfusions Prophylactic chronic RBC transfusion every 3 to 4 weeks to maintain HbS levels lower than 30% is crucial for preventing first as well as recurrent strokes in children (Johnson et al., 2007). The transfusions could either be chronic simple transfusion or prophylactic chronic RBC exchange transfusion. Prophylactic chronic transfusions are recommended for patients with chronic renal failure so as to avoid severe symptomatic anaemia and for those patients with SCD undergoing pregnancy with complications. However, prophylactic transfusion is not indicated for SCD patients with normal pregnancy (Tuck et al., 1987). 4.5 Controversial and indeterminate indications for transfusion Several situations also exist wherein the indication for red cell transfusion is controversial, uncertain, or downright injudicious in SCD management. Some examples are indicated in Table 1.   Ã‚  Ã‚  Ã‚  Ã‚  According to Hankins et al. (2005), chronic transfusion therapy is helpful in reducing the incidence of strokes in children but not the severity of strokes. In the case of acute priapism, improvement in patients has been observed after exchange or simple transfusion (Rifikind   et al., 1979). Yet, due to the ASPEN syndrome, transfusion therapy currently is only a second-line therapy in the management of priapism ( Miller et al., 1995).   Ã‚  Ã‚  Ã‚  Ã‚  RBC transfusion is a vital component in the management of symptoms and complications of SCD. It has drastically reduced the morbidity and mortality of SCD. Yet, immune-related effects such as FNHTRs (Febrile Non-Haemolytic Transfusion Reaction i.e., fever resulting from a blood transfusion) and alloimmunisation to HLAs (Human Leucocyte Antigens),   and nonimmune-related effects e.g., iron overload and transfusion-transmitted infections are serious adverse effects of the transfusion therapy that need to be attended to in SCD patients receiving transfusion (Johnson et al., 2007). Chronic transfusions could result in an inexorable accumulation of tissue iron that could become fatal if not treated (Cohen, 1987). Excess iron damages the liver, endocrine organs, and heart and may be fatal by adolescence (E Haemoglobin-related Diseases Management Strategies Haemoglobin-related Diseases Management Strategies Abstract Haemoglobinopathies or inherited disorders of haemoglobin are the most common monogenic disorders in humans. Red cell transfusion is a well accepted therapy for clinical management of the most severe form of haemoglobinopathies namely, sickle cell disease (SCD) and ÃŽ ²-thalassaemia major. Patients affected by SCD need red blood cell transfusions on a regular basis to reduce morbidity and mortality. The transfusions are administered intermittently to control or prevent a serious complication of SCD, and as a perioperative measure. Or, as a chronic procedure, transfusion strategy is applied to prevent the recurrence, or the first occurrence, of stroke which is a major crisis in SCD, and to manage pulmonary hypertension and other sources of morbidity and mortality. Exchange transfusions are used to reduce the sickle cell haemoglobin (HbS) levels during crisis. Several situations also exist wherein the indication for red cell transfusion is controversial, uncertain, or downright injudic ious. Many side effects of transfusion have been identified and methods to overcome them have been developed. Iron overload (remedy: iron chelation), and alloimmunisation (remedy: phenotypical matching of transfused blood) are two notable examples. Association of haemoglobinopathies and neurologic sequelae after transfusion is also known. At the present time, bone marrow transplant is the only curative procedure available for both SCD and ÃŽ ²-thalassaemia major. Potential therapies involving stem cell transplantation and gene techniques are being vigorously researched. A detailed discussion of the current status of clinical management strategies as applied to inherited haemoglobin-related diseases in particular, sickle cell disease and the thalassaemias, is presented in this paper. 1. Introduction Anaemia is a syndrome characterised by a lack of healthy red blood cells or haemoglobin deficiency in the red blood cells, resulting in inadequate oxygen supply to the tissues. The condition can be temporary, long-term or chronic, and of mild to severe intensity. There are many forms and causes of anaemia. Normal blood consists of three types of blood cells: white blood cells (leucocytes), platelets and red blood cells (erythrocytes). The first generation of erythrocyte precursors in the developing foetus are produced in the yolk sac. They are carried to the developing liver by the blood where they form mature red blood cells that are required to meet the metabolic needs of the foetus. Until the 18th week of gestation, erythrocytes are produced only by liver after which the production shifts to the spleen and the bone marrow. The life of a red blood cell is about 127 days or 4 months (Shemin and Rittenberg, 1946; Kohgo et al., 2008). The main causes of anaemia are blood loss, product ion of too few red blood cells by the bone marrow or a rapid destruction of cells.   Ã‚  Ã‚  Ã‚  Ã‚  Haemoglobin, a protein, present in the red blood cells is involved in the transport of oxygen from the lungs to all the other organs and tissues of the body. Iron is an important constituent of the haemoglobin protein structure which is intimately involved in the transport of oxygen. Anaemia is generally defined as a lower than normal haemoglobin concentration. The normal blood haemoglobin concentration is dependent on age and sex, and, according to the World Health Organisation (WHO) Expert Committee Report, anaemia results when the blood concentration of haemoglobin falls below 130 g/L in men or 120 g/L in non-pregnant women (WHO, 1968). However, the reference range of haemoglobin concentration in blood could vary depending on the ethnicity, age, sex, environmental conditions and food habits of the population analysed. According to Beutler and Warren (2006), more reasonable benchmarks for anaemia are 137 g/L for white men aged between 20 and 60 years and 132 g/L for older men. The value for women of all ages would be 122 g/L. Also, the lower limit of normal of haemoglobin concentrations of African Americans are appreciably lower than that of Caucasians (Beutler and Warren, 2006).   Ã‚  Ã‚  Ã‚  Ã‚  Besides the well recognised iron deficiency anaemia, several inherited anaemias are also known. These are mostly haemoglobinopathies. Adult haemoglobin is a tetrameric haeme-protein. Abnormalities of beta-chain or alpha-chain produce the various medically significant haemoglobinopathies. The variations in amino acid composition induced genetically impart marked differences in the oxygen carrying properties of haemoglobin. Mutations in the haemoglobin genes cause disorders that are qualitative abnormalities in the synthesis of haemoglobin (e.g., sickle cell disease) and some that are quantitative abnormalities that pertain to the rate of haemoglobin synthesis (e.g., the thalassemias) (Weatherall., 1969). In SCD, the missense mutation in the ÃŽ ²-globin gene causes the disorder. The mutation causing sickle cell anemia is a single nucleotide substitution (A to T) in the codon for amino acid 6. The substitution converts a glutamic acid codon (GAG) to a valine codon (G TG). The form of haemoglobin in persons with sickle cell anemia is referred to as HbS. Also, the valine for glutamic acid replacement causes the haemoglobin tetramers to aggregate into arrays upon deoxygenation in the tissues. This aggregation leads to deformation of the red blood cell making it relatively inflexible and restrict its movement in the capillary beds. Repeated cycles of oxygenation and deoxygenation lead to irreversible sickling and clogging of the fine capillaries. Incessant clogging of the capillary beds damages the kidneys, heart and lungs while the constant destruction of the sickled red blood cells triggers chronic anaemia and episodes of hyperbilirubinaemia.   Ã‚  Ã‚  Ã‚  Ã‚  Fanconi anaemia (FA) is an autosomal recessive condition, and the most common type of inherited bone marrow failure syndrome. The clinical features of FA are haematological with aplastic anaemia, myelodysplastic syndrome (MDS), and acute myeloid leukaemia (AML) being increasingly present in homozygotes (Tischkowitz and Hodgson, 2003). Cooleys anaemia is yet another disorder caused by a defect in haemoglobin synthesis.   Ã‚  Ã‚  Ã‚  Ã‚  Autoimmune haemolytic anaemia is a syndrome in which individuals produce antibodies directed against one of their own erythrocyte membrane antigens. The condition results in diminished haemoglobin concentrations on account of shortened red blood cell lifespan (Sokol et al., 1992).   Ã‚  Ã‚  Ã‚  Ã‚  Megaloblastic anaemia is a blood disorder in which anaemia occurs with erythrocytes which are larger in size than normal. The disorder is usually associated with a deficiency of vitamin B12 or folic acid . It can also be caused by alcohol abuse, drugs that impact DNA such as anti-cancer drugs, leukaemia, and certain inherited disorders among others (Dugdale, 2008).   Ã‚  Ã‚  Ã‚  Ã‚  Malaria causes increased deformability of vivax-infected red blood cells (Anstey et al., 2009). Malarial anaemia occurs due to lysis of parasite-infected and non-parasitised erythroblasts as also by the effect of parasite products on erythropoiesis (Ru et al., 2009).   Ã‚  Ã‚  Ã‚  Ã‚  Large amounts of iron are needed for haemoglobin synthesis by erythroblasts in the bone marrow. Transferrin receptor 1 (TfR1) expressed highly in erythroblasts plays an important role in extracellular iron uptake (Kohgo et al., 2008). Inside the erythroblasts, iron transported into the mitochondria gets incorporated into the haeme ring in a multistep pathway. Genetic abnormalities in this pathway cause the phenotype of ringed sideroblastic anemias (Fleming, 2002). The sideroblastic anemias are a heterogeneous group of acquired and inherited bone marrow disorders, characterised by mitochondrial iron overload in developing red blood cells. These conditions are diagnosed by the presence of pathologic iron deposits in erythroblast mitochondria (Bottomley, 2006).   2. Classification of anaemia Anaemia can be generally classified based on the morphology of the red blood cells, the pathogenic spectra or clinical presentation (Chulilla et al., 2009). The morphological classification is based on mean corpuscular volume (MCV) and comprises of microcytic, macrocytic and normocytic anaemia. (a) Microcytic anaemia refers to the presence of RBCs smaller than normal volume, the reduced MCV ( 15 would probably indicate IDA (Chulilla et al., 2009).   Ã‚  Ã‚  Ã‚  Ã‚  In macrocytic anaemia, erythrocytes are larger (MCV > 98 fL) than their normal volume (MCV = 82-98 fL). Vitamin B12 deficiency leads to delayed DNA synthesis in rapidly growing haematopoietic cells, and can result in macrocytic anaemia. Drugs that interfere with nucleic acid metabolism, such as.hydroxyurea increases MCV (> 110 fL) while alcohol induces a moderate macrocytosis (100-110 fL). In the initial stage, most anaemias are normocytic. The causes of normocytic anaemia are nutritional deficiency, renal failure and haemolytic anemia (Tefferi, 2003). The most common normocytic anaemia in adults is ACD (Krantz, 1994). Common childhood normocytic anaemias are, besides iron deficiency anaemia, those due to acute bleeding, sickle cell anaemia, red blood cell membrane disorders and current or recent infections especially in the very young (Bessman et al., 1983). Homozygous sickle cell disease is the most common cause of haemolytic normocytic anemias in children (Weat herall DJ, 1997a).   Ã‚  Ã‚  Ã‚  Ã‚  In practice, the morphological classification is quicker and therefore, more useful as a diagnostic tool. Besides, MCV is also closely linked to mean corpuscular haemoglobin (MCH), which denotes mean haemoglobin per erythrocyte expressed in picograms (Chulilla et al., 2009). Thus, MCV and MCH decrease simultaneously in microcytic, hypochromic anaemia and increase together in macrocytic, hyperchromic anemia.   Ã‚  Ã‚  Ã‚  Ã‚  Pathogenic classification of anaemia is based on the production pattern of RBC: whether anaemia is due to inadequate production or loss of erythrocytes caused by bleeding or haemolysis. This approach is useful in those cases where MCV is normal. Pathogenic classification is also essential for proper recognition of the mechanisms involved in the genesis of anaemia. Based on the pathogenic mechanisms, anaemia is further divided into two types namely, (i) hypo-regenerative in which the bone marrow production of erythrocytes is decreased because of impaired function, decreased number of precursor cells, reduced bone marrow infiltration, or lack of nutrients; and (ii) regenerative: when bone marrow upregulates the production of erythrocytes in response to the low erythrocyte mass (Chulilla et al., 2009). This is typified by increased generation of erythropoietin in response to lowered haemoglobin concentration, and also reflects a loss of erythrocytes, due to bleeding or haemolysis. The reticulocyte count is typically higher.   Ã‚  Ã‚  Ã‚  Ã‚  Sickle cell disease is characterised by sickled red cells.   The first report of SCD was published a century ago noting the presence of peculiar elongated cells in blood by James Herrick, an American physician (1910). Pauling et al. (1949) described it as a molecular disease. The molecular nature of sickle haemoglobin (HbS) in which valine is substituted for glutamic acid at the sixth amino acid position in the beta globin gene reduces the solubility of haemoglobin, causing red cells to sickle (Fig. 1). Sickling of cells occurs at first reversibly, then finally as a state of permanent distortion, when cells containing HbS and inadequate amounts of other haemoglobins including foetal haemoglobin, which retards sickling, become deoxygenated (Bunn, 1997). The abnormal red cells break down, leading to anaemia, and clog blood vessels with aggregates, leading to recurrent episodes of severe pain and multiorgan ischaemic damage (Creary et al., 2007). The high levels of inflammatory cytokines in SCD may promote retention of iron by macrophage/reticuloendothelial cells and/or renal cells. SCD care commonly depends on transfusion that results in iron overload (Walter et al., 2009). 3. Pathogenesis of anaemia Anaemia is a symptom , or a syndrome, and not a disease (Chulilla et al., 2009). Several types of anaemia have been recognised, the pathogenesis of each being unique. Iron deficiency anaemia (IDA) is the most common type of anaemia due to nutritional causes encountered worldwide (Killip et al., 2008). Iron is one of the essential micronutrients required for normal erythropoietic function While the causes of iron deficiency vary significantly depending on chronological age and gender, IDA can reduce work capacity in adults (Haas Brownlie, 2001) and affect motor and mental development in children (Halterman et al., 2001). The metabolism of iron is uniquely controlled by absorption rather than excretion (Siah et al., 2006). Iron absorption typically occurring in the duodenum accounts for only 5 to 10 per cent of the amount ingested in homoeostatis. The value decreases further under conditions of iron overload, and increases up to fivefold under conditions of iron depletion (Killip et al., 2008). Iron is ingested as haem iron (10%) present in meat, and as non-haem ionic form iron (90%) found in plant and dairy products. In the absence of a regulated excretion of iron through the liver or kidneys, the only way iron is lost from the body is through bleeding and sloughing of cells. Thus, men and non-menstruating women lose about 1 mg of iron per day while menstruating women could normally lose up to 1.025 mg of iron per day (Killip et al., 2008). The requirements for erythropoiesis   which are typically 20-30 mg/day   are dependent on the internal turnover of iron (Munoz et al., 2009) For example, the amount of iron required for daily production of 300 billion RBCs (20-30 mg) is provided mostly by recycling iron by macrophages (Andrews, 1999).   Ã‚  Ã‚  Ã‚  Ã‚  Iron deficiency occurs when the metabolic demand for iron exceeds the amount available for absorption through consumption. Deficiency of nutritional intake of iron is important, while abnormal iron absorption due to hereditary or acquired iron-refractory iron deficiency anemia (IRIDA) is another important cause of unexplained iron deficiency. However, IDA is commonly attributed to blood loss e.g., physiological losses in women of reproductive age. It might also represent occult bleeding from the gastrointestinal tract generally indicative of malignancy (Hershko and Skikne, 2009).   Ã‚  Ã‚  Ã‚  Ã‚  Iron absorption and loss play an important role in the pathogenesis and management of IDA. Human iron disorders are necessarily disorders of iron balance or iron distribution. Iron homeostasis involves accurate control of intestinal iron absorption, efficient utilisation of iron for erythropoiesis, proper recycling of iron from senescent erythrocytes, and regulated storage of iron by hepatocytes and macrophages (Andrews, 2008). Iron deficiency is largely acquired, resulting from blood loss (e.g., from intestinal parasitosis), from inadequate dietary iron intake, or both. Infections, for example, with H pylori, can lead to profound iron deficiency anemia without significant bleeding. Genetic defects can cause iron deficiency anaemia. Mutations in the genes encoding DMT1 (SLC11A2) and glutaredoxin 5 (GLRX5) lead to autosomal recessive hypochromic, microcytic anaemia (Mims et al., 2005). Transferrin is a protein that keeps iron nonreactive in the circulation, and del ivers iron to cells possessing specific transferrin receptors such as TFR1 which is found in largest amounts on erythroid precursors. Mutations in the TF gene leading to deficiency of serum transferrin causes disruption in the transfer of iron to erythroid precursors thereby producing an enormous increase in intestinal iron absorption and consequent tissue iron deposition (Beutler et al., 2000). Quigley et al. (2004) found a haem exporter, FLVCR, which appears to be necessary for normal erythroid development. Inactivation of FLVCR gene after birth in mice led to severe macrocytic anaemia, indicating haem export to be important for normal erythropoiesis.   Ã‚  Ã‚  Ã‚  Ã‚  The anaemia of chronic disease (ACD) found in patients with chronic infectious, inflammatory, and neoplastic disorders is the second most frequently encountered anaemia after iron-deficiency anaemia. It is most often a normochromic, normocytic anaemia that is primarily caused by an inadequate production of red cells, with low reticulocyte production (Krantz, 1994). The pathogenesis of ACD is unequivocally linked to increased production of the cytokines including tumour necrosis factor, interleukin-1, and the interferons that mediate the immune or inflammatory response. The various processes leading to the development of ACD such as reduced life span of red cells, diminished erythropoietin effect on anaemia, insufficient erythroid colony formation in response to erythropoietin, and impaired bioavailability of reticuloendothelial iron stores appear to be caused by inflammatory cytokines (Means, 1996;2003). Although iron metabolism is characteristically impaired in A CD, it may not play a key role in the pathogenesis of ACD (Spivak, 2002). Neither is the lack of available iron central to the pathogenesis of the syndrome, according to Spivak (2002), who found reduced iron absorption and decreased erythroblast transferrin-receptor expression to be the result of impaired erythropoietin production and inhibition of its activity by cytokines. However, reduced erythropoietin activity, mostly from reduced production, plays a pivotal role in the pathogenesis of ACD observed in systemic autoimmune diseases (Bertero and Caligaris-Cappio, 1997). Indeed, iron metabolism as well as nitric oxide (NO), which contributes to the regulation of iron cellular metabolism are involved in the pathogenesis of ACD in systemic autoimmune disorders. Inflammatory mediators, particularly the cytokines, are important factors involved in the pathogenesis of the anaemia of chronic disease, as seen in rheumatoid arthritis anaemia (Baer et al., 1990), the cytokines causing impai rment of erythroid progenitor growth and haemoglobin production in developing erythrocytes.     Ã‚  Ã‚  Ã‚  Ã‚  Anaemia is also commonly found in cases of congestive heart failure (CHF), again caused by excessive cytokine production leading to reduced erythropoietin secretion, interference with erythropoietin activity in the bone marrow and reduced iron supply to the bone marrow (Silverberg et al., 2004). However, in the presence of chronic kidney insufficiency, abnormal erythropoietin production in the kidney plays a role in the pathogenesis of anaemia in CHF.   Ã‚  Ã‚  Ã‚  Ã‚  The myelodysplastic syndromes (MDS) are common haematological malignancies affecting mostly the elderly as age-related telomere shortening enhances genomic instability (Rosenfeld and List, 2000). Radiation, smoking and exposure to toxic compounds e.g., pesticides, organic chemicals and heavy metals, are factors promoting the onset of MDS via damage caused to progenitor cells, and, thereby, inducing immune suppression of progenitor cell growth and maturation. TNF- and other pro-apoptotic cytokines could play a central role in the impaired haematopoiesis of MDS (Rosenfeld and List, 2000). Premature intramedullary cell death brought about by excessive apoptosis is another important pathogenetic mechanism in MDS (Aul et al., 1998).     Ã‚  Ã‚  Ã‚  Ã‚  SCD arising from a point mutation in the ÃŽ ²-globin gene and leading to the expression of haemoglobin S (HbS) is the most common monogenetic disorder worldwide. Chronic intravascular haemolysis and anaemia are some important characteristics of SCD. Intravascular haemolysis causes endothelial dysfunction marked by reduced nitric oxide (NO) bioavailability and NO resistance, leading to acute vasoconstriction and, subsequently, pulmonary hypertension (Gladwin and Kato, 2005).    However, a feature that differentiates SCD from other chronic haemolytic syndromes is the persistent and intense inflammatory condition present in SCD. The primary pathogenetic event in SCD is the intracellular polymerisation or gelation of deoxygenated HbS leading to rigidity in erythrocytes (Wun, 2001). The deformation of erythrocytes containing HbS is dependent on the concentration of haemoglobin in the deoxy conformation (Rodgers et al., 1985). It has been demonstrated that sickle mono cytes are activated which, in turn, activate endothelial cells and cause vascular inflammation. The vaso-occlusive processes in SCD involve inflammatory and adhesion molecules such as the cell adhesion molecules (CAM family), which play a role in the firm adhesion of reticulocytes and leukocytes to endothelial cells, and the selectins, which play a role in leukocyte and platelet rolling on the vascular wall (Connes et al., 2008). Thus, inflammation, leucocyte adhesion to vascular endothelium, and subsequent endothelial injury are other crucial factors contributing to the pathogenesis of SCD (Jison et al., 2004). 4. Current therapies for clinical management of sickle cell disease including a critical appraisal of transfusion Between 1973 and 2003, the average life expectancy of a patient with SCD increased dramatically from a mere 14 years to 50 years thanks to the development of comprehensive care models and painstaking research efforts in both basic sciences especially molecular and genetic studies, and clinical aspects of SCD (Claster and Vichinsky, 2003). The clinical manifestations of SCD are highly variable. Both the phenotypic expression and intensity of the syndrome are vastly different among patients and also vary longitudinally within the same patient (Ballas, 1998). New pathophysiological insights available have enabled treatments to be developed for the recognised haematologic and nonhaematologic abnormalities in SCD (Claster and Vichinsky, 2003). The main goals of SCD treatment are symptom alleviation, crises avoidance and effective management of disease complications. The strategy adopted is primarily palliative in nature, and consists of supportive, symptomatic and preventative approaches to therapy. Symptomatic management includes pain mitigation, management of vasoocclusive crisis, improving chronic haemolytic anaemia, treatment of organ failure associated with the disease, and detection and treatment of pulmonary hypertension (Distenfeld and Woermann, 2009). The preventative strategies include use of prophylactic antibiotics (e.g., penicillin) in children, prophylactic blood transfusion for prevention of stroke in patients especially young children who are at a very high risk of stroke, and treatment with hydroxyurea of patients experiencing frequent acute painful episodes (Ballas, 2002). Currently, curative therapy for sickle cell anaemia is only available through bone marrow and stem cell transplantation. Hematopoietic cell transplantation using stem cells from a matched sibling donor has yielded excellent results in paediatric patients (Krishnamurti, 2007). Curative gene therapy is still at the exploratory stage (Ballas, 2002). 4.1 Current and potential therapies The potential treatment strategies basically target cellular dehydration, sickle haemoglobin concentrations, endothelial dysfunction, and abnormal coagulation regulation (Claster and Vichinsky, 2003). HbS concentrations are essentially tackled through transfusions while approaches to reduce HbS polymerisation which is the main mechanism for the development of vaso-occlusion include (a) increasing foetal haemoglobin (HbF) concentration using hydroxyurea (Fig. 2), butyrate, or erythropoietin, and (b) preventing sickle cell dehydration using Clotrimazole (Fig. 3) or Mg2+pidolate. Hydroxyurea therapy increases the production of HbF in patients with sickle cell anaemia, and, thereby, inhibits the polymerisation of HbS and alleviates both the haemolytic and vaso-occlusive manifestations of the disease (Goldberg et al., 1990). Recombinant erythropoietin also increases the number of reticulocytes with HbF. Additionally, it has been observed that administration of intravenous recombinant eryt hropoietin with iron supplementation alternating with hydroxyurea enhances HbF levels more than hydroxyurea alone (Rodgers et al., 1993). As SCD is essentially characterized by an abnormal state of endothelial cell activation   that is, a state of inflammation, a pharmacologic approach to inhibit endothelial cell activation has proved clinically beneficial (Hebbel and Vercellotti, 1997). Thus, administration of sulfasalazine which is a powerful inhibitor of activation of nuclear factor (NF)-B, the transcription factor promoting expression of genes for a number of pro-adhesive and procoagulant molecules on endothelium to humans has been found to provide transcriptional regulation of SCD at the endothelium level (Solovey et al., 2001). 4.2 Red blood cell transfusion A key therapy that is applied regularly in the clinical management of patients with SCD is packed red blood cell transfusion. RBC transfusion improves the oxygen-carrying capacity which is achieved by enhancing the haemoglobin levels, causes dilution of HbS concentration thereby, reducing blood viscosity and boosting oxygen saturation. Furthermore, RBC transfusion is helpful in suppressing endogenous production of sickle RBCs by augmenting tissue oxygenation ( Josephson et al., 2007). There are two major types of RBC transfusion therapy: intermittent and chronic which are further classified as prophylactic or therapeutic. Intermittent transfusions are generally therapeutic in nature and administered to control acute manifestations of SCD whereas chronic transfusions are performed as general preventative measures to check complications of SCD. RBC transfusion given as a single dose is termed as simple transfusion. Exchange transfusion involves administration of a larger volume of RBCs replacing the patients RBCs that are simultaneously removed. Details of the various types of RBC transfusion and the major clinical indications for the same in SCD patients are listed in Table 1. 4.3 Indications for intermittent transfusions Indications for intermittent transfusions include acute manifestations of SCD, as indicated in Table 1, that require redressal through therapeutic transfusions. However, under certain circumstances intermittent transfusions could be prophylactic such as for instance, when SCD patients are transfused before specific surgeries viz., those related to pregnancy complications or renal failure (Table 1). Acute Chest Syndrome (ACS) describes a manifestation of SCD in which, due to sickling, infectious and noninfectious pulmonary events are complicated, resulting in a more severe clinical course. The diagnosis is the presence of a new infiltrate on chest radiography that is accompanied by acute respiratory symptoms. ACS accounts for nearly 25% of all deaths from SCD (Vichinsky, 2002). Repeated episodes of ACS are associated with an increased risk of chronic lung disease and pulmonary hypertension (Castro, 1996). The severe pulmonary events occurring in SCD may be precipitated by any trigger of hypoxia (Vichinsky, 2002). Transfusions are very efficacious and provide immediate benefit by reversing hypoxia in ACS. Transfusion of leucocyte-poor packed red cells matched for Rh, C, E, and Kell antigens can curtail antibody formation to below 1% (Vichinsky, 2002). Simple transfusions suffice for less severe cases; however, exchange transfusion is recommended to minimise the risk of increased viscosity. Also, chronic transfusion appears promising for prevention of recurrence in selected patients (Styles and Vichinsky, 1994). In a multicentre ACS trial, prophylactic transfusion was found to almost completely eliminate the risk of pulmonary complications (Vichinsky, 2002).   Ã‚  Ã‚  Ã‚  Ã‚  Acute Symptomatic Anaemia arises in SCD as a result of blood loss, increased RBC destruction, suppression of erythropoiesis etc. and is effectively treated with intermittent transfusion of RBCs to relieve symptoms of cardiac and respiratory distress (Josephson et al., 2007).   Ã‚  Ã‚  Ã‚  Ã‚  Aplastic Anaemia is commonly caused in SCD on account of infection of haematopoietic precursors in the bone marrow by Parvovirus B19 leading to a steep fall in RBCs. According to Josephson et al. (2007), therapeutic intermittent transfusion of RBCs is again the recommended first-line of treatment to improve total haemoglobin count and prevent cardiac decompensation. However, in those patients who are prone to fluid overload on account of cardiac or renal dysfunction an alternative transfusion strategy is to remove the whole blood and replace it with packed cells while avoiding the addition of excess volume (Josephson et al., 2007).   Ã‚  Ã‚  Ã‚  Ã‚  Acute Stroke is a high risk especially in paediatric SCD cases because of elevated cerebral flow. Enormous decline in stroke rate have occurred in children receiving intermittent simple transfusion (Adams et al., 1998). However, the identification of the stroke type would be necessary in all SCD patients in order to determine the appropriate treatment approach since the occurrence of infarctive strokes is higher in children as opposed to a higher incidence of haemorrhagic strokes in adults (Adams, 2003). 4.4 Indications for Chronic Transfusions Prophylactic chronic RBC transfusion every 3 to 4 weeks to maintain HbS levels lower than 30% is crucial for preventing first as well as recurrent strokes in children (Johnson et al., 2007). The transfusions could either be chronic simple transfusion or prophylactic chronic RBC exchange transfusion. Prophylactic chronic transfusions are recommended for patients with chronic renal failure so as to avoid severe symptomatic anaemia and for those patients with SCD undergoing pregnancy with complications. However, prophylactic transfusion is not indicated for SCD patients with normal pregnancy (Tuck et al., 1987). 4.5 Controversial and indeterminate indications for transfusion Several situations also exist wherein the indication for red cell transfusion is controversial, uncertain, or downright injudicious in SCD management. Some examples are indicated in Table 1.   Ã‚  Ã‚  Ã‚  Ã‚  According to Hankins et al. (2005), chronic transfusion therapy is helpful in reducing the incidence of strokes in children but not the severity of strokes. In the case of acute priapism, improvement in patients has been observed after exchange or simple transfusion (Rifikind   et al., 1979). Yet, due to the ASPEN syndrome, transfusion therapy currently is only a second-line therapy in the management of priapism ( Miller et al., 1995).   Ã‚  Ã‚  Ã‚  Ã‚  RBC transfusion is a vital component in the management of symptoms and complications of SCD. It has drastically reduced the morbidity and mortality of SCD. Yet, immune-related effects such as FNHTRs (Febrile Non-Haemolytic Transfusion Reaction i.e., fever resulting from a blood transfusion) and alloimmunisation to HLAs (Human Leucocyte Antigens),   and nonimmune-related effects e.g., iron overload and transfusion-transmitted infections are serious adverse effects of the transfusion therapy that need to be attended to in SCD patients receiving transfusion (Johnson et al., 2007). Chronic transfusions could result in an inexorable accumulation of tissue iron that could become fatal if not treated (Cohen, 1987). Excess iron damages the liver, endocrine organs, and heart and may be fatal by adolescence (E