Monday, January 27, 2020
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.      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).      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.      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.      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).      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).      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).      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).      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).      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.      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.      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).      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).      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.      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.      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.      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).      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).      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).      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).      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.      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).      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.      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).      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.      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.      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).      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).      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).      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).      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).      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.      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.      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).      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).      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.      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.      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.      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).      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).      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).      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).      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.      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).      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
Sunday, January 19, 2020
The American Education System; Cause For Rebellion :: essays research papers fc
The American Education System; Cause for Rebellion      If America's Schools are to meet the needs of the twenty first century, they must be reinvented. It is not enough to try to fix the schools; they must be reconstructed in both fundamental and radical ways. The school system must be restructured. The future of the American public school system is significant because the maintenance of an informed and productive citizenry is vital to the future of this country. Historically Americans have strongly asserted the importance of public schools in a democracy and despite growing disdain for the perceived value of the school system, public schools remain central to democracy in the United States.      For more than a century, America's public schools have been an indispensable source of the country's strength. Public education has allowed citizens to become productive members of society by providing them with the skills and knowledge necessary for the labor force. Schools prepare students to be literate, informed and reasoning citizens. According to Philip Schlechty, author of Schools for the twenty-first century, â€Å"Public schools are the ties that bind this pluralistic society into a nation. Our Nation's thirty-sixth president, Lyndon B. Johnson, also believed that there is no institution more fundamental to American society and democracy than its public schools.†(36)      Public schools are the cornerstone of America's future. The development of youth's knowledge, skills and social dispositions has always been critical to the country's success. In the next century, America's youth will play an increasingly important role in the country's survival and well-being. By the year 2025, one out of five Americans will be 65 or older, and by the year 2040, one out of four Americans will be 65. In less than 15 years, the first baby boomers will reach the age of 65 (Peterson 64). It is clear that the economic success of America will be in the hands of youth to unprecedented extent. It is time to invest in education in order to maintain the American way of life.      In the competitive knowledge-based world of the twenty-first century, the education of America's youth will be more important than ever. More responsibility will be placed on schools because of greater diversity in classrooms, languages, preparedness, motivation, and the dynamics of the future workplace. Schools also must assume more responsibility because of increasing enrollment. Entering the 1996-1997 school year, there is an all time high enrollment of 51.7 million students in public schools throughout the country (Good 6). Because of enhanced enrollment and technological advances, there is more material that needs to be taught if students are to be competitive and productive in the future job market.
Saturday, January 11, 2020
Nortel Case Report Essay
The company also used to be affiliated with AT&T/Western Electric until Western was forced to sell its stake in 1949. In 1976, the company changed its name from Northern Electric to Northern Telecom Limited, and shifted its concentration on digital technology. In 1977, Nortel introduced its DMS line of digital central office telephone switches. Nortel ended its long relationship with AT&T in 1984, a year after deregulation named. Bell Canada Enterprises the parent company to Northern Telecom. In 1998, the company acquired Bay Networks and changed its name to Nortel Networks. In the late 90’s, Nortel’s sales of fiber optic network gear was predicted to help their sales, but the market became saturated very quickly. At the height of Nortel’s first 100 years the company amassed for more than a third of the total valuation of all companies listed on the Toronto Stock Exchange (TSX), but once the Internet bubble passed, the company fell into ethical debacle. Nortel Networks Corporation, or formally known as Northern Telecom Limited was one of the largest telecommunications equipment companies in the world prior to its filing for bankruptcy protection on January 14th, 2009. During times of functionality, they specialized in multinational telecommunications equipment manufacturing. The company is based in Canada out of Mississiauga, Ontario, Canada. Their biggest rival always was Global System Mobile (GSM). Through the early 1990s, the company invested heavily in Code Division Multiple Access (CDMA) in attempt to grow in European and Asian markets. This did not pan out so well as Nortel’s losses amounted to $27. 3 billion by 2001â€â€causing them to lay off two-thirds of the workforce. From 2000 through 2003 there was a period of fiscal irresponsibility resulting from the work of the company’s administrators. Initially in 2000, they falsified their fourth-quarter earnings by $1 billion to meet market expectations and selectively reversing certain revenue entries. In 2002, administrators discovered $300 million in excess reserves being carried over and swept it under the rug for future benefit in addition to establishing another $151 million in unnecessary reserves. In 2003, administrators directed the release of at least $490 million of excess reserves to boost earning, fabricate profits, and pay bonuses. Losses turned to profits during this year thanks to the shifty methods taking place. Later in that year, administrators mislead investors as to why Nortel was conducting a purportedly â€Å"comprehensive review†of its assetsâ€â€attributed by restatement $948 million in liabilities. They said restatement was caused solely by internal control mistakes instead of the truth that there was intentional improper handling of reserves which needed to remain hidden. 2 On October 23rd, 2003, the company announced that Nortel would restate its financials for fiscal years 2000, 2001, and 2002. Shortly after this restatement, the major players of Nortel’s administration that were responsible for all of this were exposed through an independent investigation. In March 2004, The CFO and controller were suspended, in addition to the announcement of further restatements and revisions; they were terminated a month later in April 2004. A restatement in early 2005 showed approximately $3. 4 billion in misstated revenues and another $746 in liabilities. In late 2005, Nortel admitted that restatements were the result of management fraudâ€â€beginning the downturn of their stock. The company ended up restating financials four times over four years, replacing senior management, and instituting a comprehensives remediation program designed to ensure proper accounting and reporting practices. Eventually on October 15th, 2007, Nortel agreed to settle by paying a $35 million civil penalty and admitting to violations of the antifraud, reporting, books and records, and internal control provisions of the federal securities laws. 2 On June 25th, 2009, Nortel’s price dropped to 18. 5 cents a share down from a high of $124. 0 in 2000. The company decided that month that they would discontinue operations and sell off all of its business units. Nortel’s CDMA wireless business and LTE access technology were sold to Ericsson, and Avaya purchased Nortels Enterprise business unit. Major Players in the Scandal: The major players in this scandal were the four members of the senior management: CEO Frank Dunn, CFO Douglas Beatty, controller Michael Gollogly, and ass istant controller Maryanne Pahapill. CEO Frank Dunn, who is also a certified management accountant. Dunn was mainly involved in the improper use of reserves from 2000 to 2003. CFO Douglas Beatty, controller Michael Gollogly, and assistant controller Maryanne Pahapill were also involved in this management fraud. 2 The Royal Canadian Mounted Police in Toronto arrested ex-CEO Frank Dunn, ex-CFO Douglas Beatty, and former corporate controller Michael Gollogly on seven counts of fraud. Including charges â€Å"fraud affecting public market; falsification of books and documents; false prospectus, pertaining to allegations of criminal activity within Nortel Networks during 2002 and 2003. Magnitude of the financial issue: Nortel at its peak was one of the best companies that Canada had ever seen. Just like ENRON and other financial frauds at the time, Nortel appeared to be a shining example of success in the corporate world. Again like ENRON, Nortel grew through a strategy of aggressive expansion and purchasing of smaller companies in order to create a massive conglomerate. During the good times Nortel was the largest technology company and the most valuable company in Canada. Nortel accounted for over one third of the entire aluation of the Toronto Stock Exchange. The Toronto Stock Exchange is the Canadian equivalent of the New York Stock Exchange and holds the most influential stock market in Canada. Nortel employed about 95,000 employees worldwide. About 26,000 of those workers based in Canada alone. Nortel at one point had a market capitalization of almost C$400 billion. Nortel had set up pensions and healthcare protection for its employees. All of these were lost to either the restructuring under Frank Dunne which left about 60,000 employees without jobs or the bankruptcy that followed in 2009. Canadian government officials and regulators identified how destructive a full failure of Nortel would be on the Canadian economy. The Canadian government through the Export Development Canada project tried to lend money to the falling giant. However the Canadian government could not cover all of Nortel’s debt obligations. Nortel owed about $107 million and the EDC (Export Development Canada) could only supply about $30 million in short term loans. This $107 million interest payment accounted for about 4% of Nortel’s cash and put the company into bankruptcy. The world financial crisis of 2008 had put too much strain on Nortel and they were forced to begin liquidation. Public auditor: The auditors involved with this case were Deloitte and Touche. In documents from the fraud case, which is still being heard by the Royal court in Canada, Deloitte claims that they were not given proper documentation by Nortel. Deloitte claims that they did not have pertinent information which should have been provided by administrators at Nortel. Deloitte raised concerns to the audit board of Nortel in 2003 when Nortel turned a profit after Frank Dunne’s restructuring of the company. Deloitte raised awareness of potential fraud and did their duty in that respect. However further investigation conducted has implicated Deloitte in the financial reporting irregularities in Nortel which some have claimed dates back to the time of CEO Roth who held office before Dunne. Information coming out of the case states that even if transactions were deemed suspicious, they still signed off on the verity of the financial reports. Frank Dunne and some of his officers are now charged with fraud by both the SEC and the OSC which regulate the American and Canadian markets respectively. The case is currently still under review in the Royal court of Canada and civil charges have been brought in the United States. Fraud Triangle Nortel had experienced tremendous growth throughout the 1990s, allowing it to expand operations worldwide. Nortel’s expansion came during the telecommunication and technology bubble of the 1990s that inflated stock prices of companies in those sectors. Frank Dunn had taken over for the previous CEO, John Roth, in November 2001 during the telecommunication bubble bust. Dunn felt pressured to maintain the high stock price because it accounted for over one third of Nortel’s value2. Nortel management was also incentivized to post profits that produced executive bonuses with over $7. 8million going to Dunn alone. The primary members of the Nortel fraud were able to commit the fraud because, as executive officers and controllers, they were able to go around the internal controls of the company. That allowed them to implement many accounting practices that did not comply with GAAP. Nortel management’s rationalization for these fraudulent practices must have been that they needed to maintain the high stock price in order for the company to continue operating. Moral Breach and Ethical Issues As a publicly traded company, Nortel had the responsibility of fairly reporting the company’s true financial data to stockholders and potential investors. Dunn, Beatty, Gollogly and Pahapill breached this responsibility by establishing earnings management accounting strategies to manipulate Nortel’s revenues. Nortel management also actively sought to inflate earnings to trigger very large bonuses for key members of management. Perhaps, if these incentives did not exist then there would be less motivation to commit the fraud. Finally, Nortel’s auditor for over a century, Deloitte and Touche, has come under scrutiny by the defense lawyers in Dunn, Gollogly and Beatty’s civil trial in Canada this year. The defense claims that Deloitte approved of all major accounting adjustments that Dunn and his team had engaged in. Summary of Legal Actions On April 28th, 2004, Dunn and his fraud partners were fired for financial mismanagement2. On March 12th, 2007 the SEC filed civil charges against Dunn, Beatty, Gollogly and Pahapill for repeatedly engaging in accounting fraud to bridge gaps between Nortel’s true performance, its internal targets, and market expectations. Dunn and Beatty were charged with violating the officer certification agreement that was established by the Sarbanes-Oxley Act. Nortel settled with SEC on October 15, 2007 by consenting to be prescribed from violating the antifraud, reporting, books and records, and internal control provisions of the federal securities laws. Nortel paid $35million to the SEC, and $1million to the Ontario Securities Commission to establish a Fair Fund for affected shareholders. Finally, Canadian authorities arrested and charge Dunn, Beatty and Gollogly with seven counts of fraud. Their trial began on January 16th, 2012. Current Status: Nortel, once known as the largest telecommunications manufacturer in the world, filed for bankruptcy in 2009. Now three years later, the period of bankruptcy continues as the company discloses their every operating report highlighting each cash receipt and disbursement. When Nortel went bankrupt, executives believed that selling all business assets would be the best and easiest way to fight debt. Recently, Nortel has netted $7. 7 billion from selling its patents and businesses. As stated on their website, â€Å"Nortel remains focused on maximizing value for its stakeholders, including the sale of its remaining assets, resolution of claims, the wind-down of its global operations and entities, resolution of allocation matters with respect to the sale proceeds, and other significant restructuring activities toward the conclusion of the creditor protection proceedings. †The case for Nortel executives Dunn (ex CEO), Beatty (ex CFO) and Gollogy (ex controller), who were charged with fraud for affecting the public market and falsifying books and documents to earn larger bonuses, is still in trial. In February, a former Vice President of Nortel testified in court against executives stating that they had asked him to use questionable accounting methods to manipulate the company’s earnings. Although those who committed the crime have been charged, thousands of employees will still be left without pension plans and jobs. Nortel has spent over $20 million on retirement package these past two year, but unfortunately the company will stop the pension plan and disability program payments as it continues to sell away its businesses. By the end of 2011, Nortel was split into regional entities – Nortel Networks Limited in Canada and Nortel Networks Inc in the United States, causing disagreements over how to split $7. 5 billion that was earned by selling many assets and patents other corporations such as Apple and Microsoft Corp. The following charts, graphs and financial statements analyze Nortel’s current status. Case Study Questions and Solutions: 1. Dunn is a certified management accountant. Based on the facts of the case, which provisions of the IMA’s Statement of Ethical Professional Practice that was discussed in chapter 1 have been violated? Dunn violates many of the provisions of the IMA’s statement of Ethical Professional Practice they are as follows: 1. Perform professional duties in accordance with law, regulations and technical standards. 2. Provide decision information that is accurate, clear, concise and timely 3. Retain from engaging in any conduct that would prejudice carrying out any duties ethically. 4. Abstain from engaging in or supporting any activity that might discredit the profession. 5. Communicate information fairly and objectively. 6. Disclose all relevant information, that could reasonably be expected to influence an intended users understanding of the reports analyses or recommendations. 7. Disclose delays or deficiencies in information timeliness processing or internal controls in conformance with organization policy and/or applicable law. He violated these by selective reversal of revenue entries in 2000. Followed by concealing the reserves in 2002, which violated GAAP, and then avoided posting a profit so the company wouldn’t have to pay out bonuses. In 2003 Dunn released the reserves to falsely report a profit, which allowed them to eports a profit a quarter earlier than expected, and to pay out more bonuses to senior management. Also in 2003 he misled the investors about why Nortel had restated its financials in order to avoid uncovering the unethical management techniques him and his team had been using. All of these actions take away Dunn’s integrity and credibility in the field of manageria l accounting, which are two of the standards the IMA sets out. Dunn failed to meet his professional code of conduct and his company suffered because of it. 2. What are the responsibilities of an auditor to detect fraud? How were those responsibilities compromised by the actions of Nortel’s management? It is the auditors responsibility to report fraud if they find it, however in this case the actions of Nortel’s management made it difficult for the auditors to do their job. The false financial statements and hiding of money veiled the problems of the company from the auditors. Once there was a hint of the fraud the auditors found it and perused the trail, taking the ethical route and also following the code of conduct. It was their investigation that brought down the fraudulent executives and forced the company to restate its financials properly. This would eventually lead to the failure of Nortel. Nortel made materially false and misleading statements and omissions in connection with the quarterly reviews and materially misstated annual audits of financial statements. This caused the auditors to not be able to properly do their job, and review the statements. 3. Describe the incentives that created pressure on Nortel to manage earnings. Considering the role of Nortel’s management in this regard, discuss whether it met its corporate governance obligations as discussed in previous chapters. The incentives that drove Nortel to manage its earning where greed of the management team, the pressure to deliver bonuses, the pressure to survive an economic downturn, and the pressure to make the company seem like a good investment to both current and potential investors. In an economic climate of intense competition and corporate greed the management at Nortel fell victim to their vices and allowed the pressure to perform to overwhelm their priorities. This caused them to put their own greed and personal ambition before the well being of the company. Nortel did not meet its corporate governance obligations. It did not follow any internal rules of how to run the business. It ignored any corporate ethics they might have. It lied to stakeholders several times by misstating the financials. They did not follow the professional code of conduct of their careers and also did not follow industry standards. They broke the law. No one inside the company caught the fraud therefore their internal controls where not effective. Each of these immoral acts is a case where corporate governance has failed. 4. The final quote in the case characterizes Nortel’s failure as â€Å"just another casualty of capitalism. Do you agree with this statement? Why or why not? How would you characterize the cause of the failure at Nortel? I would argue that Nortel is not just another casualty of capitalism. Nortel did not function in a system of free market capitalism where the government had absolutely no regulation and let the markets function however they wanted. The capitalism system of North America is more of a mixed economy, which combines public and private ownership of companies, and also provides government regulation and intervention to prevent and deal with fraud. Even in a free market the system is meant to come to an equal balance of supply and demand, which cannot be reached if there is fraud involved since the supply has been inaccurately disclosed by the senior management at Nortel. I would characterize this failure as one of humanity. It was not the economic system that allowed this fraud to take place, but the greed of the people and a social environment that ties success so strongly to wealth. It was the social pressure and the effect of human nature that led to Nortel’s demise. . The case discusses how Nortel’s managers prioritized themselves over the shareholders, which, in part, lead to the company’s failure. What should be a company’s first priority? A company’s first priority should be following their code of ethics. The second priority should be the shareholders, followed by the management and other employees. This hierarchy ensures that all the business that is done with be both moral and legal , meaning there is no room to commit fraud and damage the company. In this way you are putting the shareholders first, because by providing a stable and healthy company the shareholders will see an investment that will be able to reach its highest potential. 6. Was Nortel’s settlement a fair penalty? Should the SEC have imposed harsher or more lenient sanctions? Should these sanctions have been on the managers, on Nortel as a whole, or both? A fair settlement would offer compensation to all those who were hurt by this fraud. Groups that may have been hurt could be shareholders, employees and customers. Deciding what is a fair compensation is a little more difficult, however as much of what these people lost as possible should be returned to them. As for the managers who created the problems and took part in the fraud should face a sentence of termination from their company, loss of license (if applicable) and jail time. The company and the individual managers have both failed stakeholders and should both be held accountable. In the case of Nortel specifically the stockholder settlement goes with these guidelines, as for the managers their trial is still ongoing and therefore no sentenced has been given to them yet.
Friday, January 3, 2020
The Day Is Done Poem Analysis - 1005 Words
Explication of â€Å"The Day is Done†by Henry Wadsworth Longfellow The poem â€Å"The Day is Done,†by Henry Wadsworth Longfellow, discusses an exhausted speaker’s wish to hear the work of a simple poet with the expectation that this will relieve his tired state. The steady, calming pace and slightly wistful tone provide the perfect background for the beautiful imagery of this poem, expressed through similes and figurative language. ‘The Day is Done†includes comments on reputation, life’s struggles, and the benefits of poetry and art in general. This lovely poem’s gentle verses leave the reader soothed and care-free. The poem starts by informing the reader that â€Å"the day is done†(Longfellow 575) and darkness has fallen. The speaker is looking†¦show more content†¦However, the tone is not forceful. â€Å"The Day is Done†echoes qualities of a lullaby, gently pulling the reader through the story, moving towar ds the end of the night, moving towards rest. While the poem does not have a set meter, it still flows easily. Each stanza has four lines and the second and fourth lines of the stanzas often use similar metrical patterns, such as in the ninth stanza where the second line reads, â€Å"The restless pulse of care†and the fourth line reads, â€Å"That follows after prayer.†(Longfellow 576). The tone is also aided by the rhyme scheme. The second and fourth line always share the same end rhyme, however the first and third lines do not. This pattern gives the poem a nice flow, which draws the reader along at a steady pace. The feeling of sadness is exemplified through the setting of twilight (with the threat of darkness approaching) and through the rain and mist discussed multiple times throughout the poem. The use of a narrative speaker also makes the reader more aware of the tone. Having the speaker talk in the first person point of view draws sympathy and increases the r eader’s identification with the speaker. Beautiful imagery and figurative language also increase the reader’s connection with the speaker, painting clear pictures of familiar scenes. The speaker often uses physical examples to illustrate an emotional point, as in the third stanza when the speaker employs a simile, saying, â€Å"A feeling of sadness and longing, / That isShow MoreRelatedThe Day Is Done Poem Analysis941 Words  | 4 PagesHenry Wadsworth Longfellow’s short poem, â€Å"The Day is Done,†the reader is given a glimpse of the Romantic era of American poetry. Structurally, it does contain many elements of this era, namely the playful usage of verse or rhyme schemes. However, this is where Longfellow’s work seems to end in relation to typical Romantic poetry. Upon further examination of this poem, the execution of subject matter does not seem to fit a typical Romantic era poems. Since Romantic poems overly gush with inner thoughtsRead MoreComparing Modern And Traditional Poems1359 Words  | 6 PagesModern and Traditional Poems Literature always reflects the reality in the contemporary world. There have been a number of poetic creations from remarkable writers who could skillfully fabricate works which echo the multidimensional aspects of the existing world. However, apart from considering a poem’s worth by linking to its social and cultural contexts, an independent analysis is quite possible. It is in this context that a deep textual analysis of the formal features of the poems becomes significantRead MoreAt Castlewood Emily Bronte Analysis1142 Words  | 5 Pagesï » ¿Jackie Bako Mrs. Boyd AP English IV 15 September 2013 Poetry Analysis Paper Emily Brontà «, born in Yorkshire, the fifth child of six children. Growing up, she always had a keen interest in writing poetry. With her collection of different poems, At Castle Wood was one. In Brontà « s poem, At Castle Wood, she establishes a sorrowful theme through the use of imagery, Brontà « s tone of somber throughout her poem and also her use of end rhyme, for the purpose of creating a simple yet powerfulRead MoreA Poison Tree Analysis Essay977 Words  | 4 PagesRunning head: Analysis of William Blake’s A Poison Tree (1794) Analysis of William Blake’s A Poison Tree (1794) Jayne Courtney Kendall Brandman University Abstract This analysis is going to explore each segment to better understand the meaning the author was trying to express and the lessons that we in these words that transcends through all ages. The exploration and analysis will look further in to what we can take away from this writing and lesson we can learn in order for our soul’sRead MoreWilliam Blake Songs of Innocence Experience1256 Words  | 6 Pagesâ€Å"The Chimney Sweeper†Songs of Innocence amp; Experience analysis with, William Blake In 1794 William Blake’s work was known and published as a collection of poems that were put together as one book called Songs of innocence amp; Songs of Experience. In the collection Blake titles a poem, â€Å"The Chimney Sweeper†, and this one is viewed in two ways: Innocence and experience. In the book of innocence Blake shows how poor innocent children are being abused and mistreated during this time era. In SongsRead MoreEssay about The Influence of the Common Scotish Life on Robert Burns1353 Words  | 6 Pageschildren†(The Calgary Burns Club) In order to make a living the Burns family had to become farmers in order to bring in a larger salary to keep afloat. Back in that day and time the whole family had to work together to bring in wages. Robert Burns was the oldest of the family and so he had to work by his father’s side. Most of his poems were about the natural world, and was influenced heavily by the outdoor work. Henry Mackenzie described Bur ns as a â€Å"Heaven-taught ploughman.†(BBC News) But we mustRead MoreAnalysis Of The Poem I Was The Hardest Paper For Me 899 Words  | 4 Pagesif I was going to have another situation like in my literary analysis. I found that I often discouraged myself several times why writing. The paper I want to focus on in this reflection is my Analysis paper. The analysis paper was by far the hardest paper for me. Not because I did not know how to do it or even for the simple fact that I did not want to do it. I was hard because I could not figure out which way I wanted to portray the poem I decided to work with. During the writing I found myself startingRead MoreCharacter Analysis Of Alfred s Ulysses 1043 Words  | 5 PagesCharacter Analysis of Alfred Tennyson s Ulysses I soon researched the character ‘Ulysses’ after reading the poem written by Alfred Lord Tennyson. In my research on the character of Ulysses, I discovered there are different aspects that can be looked at from different viewpoints of which can affect whether you see him as Ulysses the hero, or as Ulysses the man. Lending to the reality that even though somebody may be your hero, he is still human underneath. In my analysis of the character UlyssesRead More Analysis of Out, Out by Robert Frost Essay591 Words  | 3 PagesAnalysis of Out, Out by Robert Frost Robert Frost tells a disturbing story in Out, Out, --, in which a little boy loses his life. The title of the poem leaves the reader to substitute the last word of the title, which some would assume would be out because of the repetition. The title is referring to the boy exiting the living world. Frost drags the readers mind into the poem with the imagistic description of the tools and atmosphere the little boy is surrounded by. Frost describesRead MoreAnalysis of I wondered Lonely as a Cloud by William Wordsworth1309 Words  | 6 PagesIn vacant or in pensive mood, They flash upon that inward eye Which is the bliss of solitude; And then my hearth with pleasure fills, And dances with the daffodils. Analysis: Wordsworth had nature as his religion, and that was the main theme of his work and also a characteristic of romanticism. And it’s also very clear on this poem. As literary devices, we have Alliteration on the second line of the first stanza, alliteration and assonance on the fifth line of the first stanza and personification
Subscribe to:
Posts (Atom)