Haemoglobinopathies - Free Essay Example

Sample details Pages: 25 Words: 7474 Downloads: 5 Date added: 2017/06/26 Category Statistics Essay Did you like this example? 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 ÃŽÂ ²-thalassaemia major. Patients affected by SCD need red blood cell transfusions on a regular basis to reduce morbidity and mortality. Don’t waste time! Our writers will create an original "Haemoglobinopathies" essay for you Create order 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 injudicious. 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 curati ve procedure available for both SCD and ÃŽÂ 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 ÃŽÂ ²-globin gene causes the disorder. The mutation causing sickle cell anemia is a single nucleotide substitution (A to T) in the codon for amino acid 6. The substitution converts a glutamic acid codon (GAG) to a valine codon (GTG). The form of haemoglobin in persons with sickle cell anemia is referred to as HbS. Also, the valine for glutamic acid replacement causes the haemoglobin tetramers to aggregate into arrays upon deoxygenation in the tissues. This aggregation leads to deformation of the red blood cell making it relatively inflexible and restrict its movement in the capillary beds. Repeated cycles of oxygenation and deoxygenation lead to irreversible sickling and clogging of the fine capillaries. Incessant clogging of the capillary beds damages the kidneys, heart and lungs while the constant destruction of the sickled red blood cells triggers chronic anaemia and episodes of hyperbilirubinaemia. 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 ( 82 fL) reflecting decreased haemoglobin synthesis.   Thus, it is usually associated with hypochromic anaemia. Microcytic anaemia can result from defects either in iron acquisition or availability (Iolascon et al., 2009), or disorders of haeme metabolism or globin synthesis (Richardson, 2007). The differential diagnosis for microcytic anaemia includes iron deficiency anaemia (IDA), thalassaemia, ACD, and rarely sideroblastic anaemia (Chulilla et al., 2009). Microcytosis without anaemia is characteristic of thalassaemia trait. The red blood cell distribution width (RDW) obtained with haematological analysers provides the index of dispersion in the erythrocyte distribution curve and complements MCV values. RDW is helpful to differentiate between thalassaemia and IDA. RDW is normal in thalassemia; on the contrary, microcytic anemia with RDW 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 (Weatherall 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 r eticulocyte 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 delivers iron to cells possessing specific transferrin receptors such as TFR1 which is found in largest amounts on erythroid precursors. Mutations in the TF gene leading to deficiency of serum transferrin causes disruption in the transfer of iron to erythroid precursors thereby producing an enormous increase in intestinal iron absorption and consequent tissue iron deposition (Beutler et al., 2000). Quigley et al. (2004) found a haem exporter, FLVCR, which appears to be necessary for normal erythroid development. Inactivation of FLVCR gene after birth in mice led to severe macrocytic anaemia, indicating haem export to be important for normal erythropoiesis. 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 ACD, it may not play a key role in the pathogenesis of ACD (Spivak, 2002). Neither is the lack of available iron central to the pathogenesis of the syndrome, according to Spivak (2002), who found reduced iron absorption and decreased erythroblast transferrin-receptor expression to be the result of impaired erythropoietin production and inhibition of its activity by cytokines. However, reduced erythropoietin activity, mostly from reduced production, plays a pivotal role in the pathogenesis of ACD observed in systemic autoimmune diseases (Bertero and Caligaris-Cappio, 1997). Indeed, iron metabolism as well as nitric oxide (NO), which contributes to the regulation of iron cellular metabolism are involved in the pathogenesis of ACD in systemic autoimmune disorders. Inflammatory mediators, particularly the cytokines, are important factors involved in the pathogenesis of the anaemia of chronic disease, as seen in rheumatoid arthritis anaemia (Baer et al., 1990), the cytokines causing impairment of erythroid p rogenitor 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 ÃŽÂ ²-globin gene and leading to the expression of haemoglobin S (HbS) is the most common monogenetic disorder worldwide. Chronic intravascular haemolysis and anaemia are some important characteristics of SCD. Intravascular haemolysis causes endothelial dysfunction marked by reduced nitric oxide (NO) bioavailability and NO resistance, leading to acute vasoconstriction and, subsequently, pulmonary hypertension (Gladwin and Kato, 2005).    However, a feature that differentiates SCD from other chronic haemolytic syndromes is the persistent and intense inflammatory condition present in SCD. The primary pathogenetic event in SCD is the intracellular polymerisation or gelation of deoxygenated HbS leading to rigidity in erythrocytes (Wun, 2001). The deformation of erythrocytes containing HbS is dependent on the concentration of haemoglobin in the deoxy conformation (Rodgers et al., 1985). It has been demonstrated that sickle monocytes are a ctivated 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 (Engle, 1964). 5. Critical review of thalassemias : (i) Molecular pathogenesis The large number of inherited haemoglobin disorders known today include (a) those related to anomalies in the haemoglobin structure e.g., sickle cell disease, and (b) the thalassemias whose hallmark is globin-chain deficiency of one or other of the globin chains of adult haemoglobin in erythroid cells. 5.1 ÃŽÂ ²-Thalassaemias These are a set of genetic disorders inherited as simple codominant traits affecting haemoglobin synthesis. Depending on the haemoglobin chain affected, 2 types of thalassemia are recognised: ÃŽÂ ±-thalassaemia and ÃŽÂ ²-thalassaemia. Homozygous ÃŽÂ ²-thalassaemia is marked by a quantitative deficiency of the ÃŽÂ ²-globin chains in the erythroid cells. A complete absence of the ÃŽÂ ²-globin chains occurs in homozygous ÃŽÂ ²o-thalassaemia whereas in homozygous ÃŽÂ ²+-thalassaemia the ÃŽÂ ²-globin chains are present at less than 30% of normal. Accounting for nearly 90% of the cases, ÃŽÂ ²+-thalassaemia is the most commonly observed form of ÃŽÂ ²-thalassaemia. The condition is termed thalassaemia major when there is microcytic hypochromic anaemia with severe haemolysis, hepatosplenomegaly, skeletal deformities and iron overload. ÃŽÂ ²-thalassaemia homozygotes exhibit severe transfusion-dependent anaemia in the very first year of life. Homozygotic individ uals having a relatively benign clinical phenotype and surviving with or without transfusion are described as thalassaemia intermedia (Weatherall, 1969). The thalassaemias, thus, encompass a wide gamut of clinical disability from intrauterine death to a mild anaemia with no overt symptoms (Weatherall, 1997b). The coexistence of   ÃŽÂ ± -thalassaemia leading to reduction in the synthesis of ÃŽÂ ±-globin chains, and a genetic predisposition to produce high levels of HbF, could be important factors for the extensive phenotypic variability described above (Weatherall, 1996). The milder form of thalassaemia intermedia is the result of a lesser imbalance in globin chain synthesis probably the result of residual ÃŽÂ ² -globin chain synthesis due to mild mutation or due to reduced synthesis of ÃŽÂ ±-globin chains due to co-inheritance of ÃŽÂ ±-thalassaemia (Nadkarni et al., 2001). Persons having the heterozygous form of the disorder are usually asymptomatic but can be recognised by typical abnormalities of red cell morphology (shown in Fig.4) and indices (Spritz and Forget, 1983). Compared to the heterozygous form of ÃŽÂ ²-thalassaemia, a larger imbalance exists in the ÃŽÂ ±- to ÃŽÂ ²-globin chain synthesis in the homozygous ÃŽÂ ²-thalassemia or Cooley anaemia. The excess ÃŽÂ ±-globin chains are liable to precipitate, causing damage to the ÃŽÂ ²-thalassemic red cell membrane and affecting erythropoiesis. Important manifestations of homozygous ÃŽÂ ²-thalassemia are severe chronic microcytic haemolytic anaemia and hepatosplenomegaly due to extramedullary haematopoiesis (Spritz and Forget, 1983). As many as 175-200 molecular mutations affecting the ÃŽÂ ²-globin gene complex are involved in creating the ÃŽÂ ²-thalassaemia syndromes with the resultant altered synthetic ratios of ÃŽÂ ±- to ÃŽÂ ²-globin chains, precipitation of excess unbalanced ÃŽÂ ±-globin chains, and programmed cell death of erythroid precursors (Steinberg and Rodgers, 2001; Gambari, 2010). Hence, the pathogenetic basis of the clinical diversity of the ÃŽÂ ²-thalassaemia syndromes essentially rests with the striking heterogeneity of mutations in the ÃŽÂ ²-globin gene (Thein, 1993). The -158 (C ÃÆ'   T) substitution in the GÃŽÂ ³ gene has been found to be linked to the increase in HbF synthesis leading to less severe disease in thalassaemia intermedia (Gilman and Huisman, 1985; Ragusa et al., 1992). 5.2 Red blood cell transfusion and iron overload Regular RBC transfusions have proved to be efficacious in the treatment of ÃŽÂ ²-thalassemia by nullifying the complications of anaemia and compensatory bone marrow (BM) expansion. However, thalassaemias are also complicated by physiological iron overload which gets exacerbated by blood transfusion and causes various endocrine diseases, liver cirrhosis, cardiac failure and also death (Engle, 1964). Complemented with iron-chelating therapy (e.g., deferoxamine) for iron overload, the prognosis of thalassemia major has become dramatic (Olivieri and Brittenham, 1997).  Ãƒâ€šÃ‚   Recently, the mechanism of iron overload in the absence of transfusion in thalassaemia has been unraveled by Tanno et al. (2007) who observed that the overproduction of the protein GDF15 suppresses the production of the liver protein, hepcidin in thalassaemia patients which eventually leads to an increase in the uptake of dietary iron in the gut. This information could translate into new diagnostic and therapeutic tools in the future. 6. Critical review of thalassemias : (ii) Clinical management therapies ÃŽÂ ²-thalassaemia syndromes are the most common genetic diseases worldwide. Improvements in treatment strategies have resulted in good prognosis. Yet, disease- and treatment-related complications get exacerbated over time, increasing morbidity and curtailing life expectancy of the patients. Currently, the only curative treatment available for thalassaemia is stem cell transplantation (SCT) (Gaziev et al., 2008) which is a gold standard in treating the disease. Many challenges exist for transplantation therapy including graft versus host disease (GVHD), rejection of the donated stem cells, and infections while a major limitation for SCT is finding HLA-matched blood-related donors viz., siblings. Currently available high-resolution HLA-typing could minimise rejection and GVHD by matching major as well as minor HLA (Gaziev et al., 2008). The advanced techniques of HLA-typing can also identify unrelated but suitable voluntary donors. Intermittent red blood cell transfusion is the recommended mode of treatment for people who have moderate or severe thalassaemias. ÃŽÂ ²-thalassemia major, or Cooleys anaemia require regular blood transfusions. 6.1 Emerging Therapies Gene therapy for treatment of thalassaemia is still evolving. Research is focussed on finding a potential treatment of ÃŽÂ ² -thalassemia based on globin gene transfer. One of the aims of the genetic research is to trigger the production of HbF in adults to make up for the lack of healthy adult haemoglobin. The molecular mechanisms that initiate the change in gene expression during the switch from foetal (HbF) to adult (HbA) have been partially elucidated. Several chemical compounds able to reactivate HbF synthesis in vitro and in vivo in adult bone marrow have been identified (Testa, 2009). Induction of HbF to treat thalassaemia is a novel therapeutic strategy especially for those patients who are resistant to conventional therapy that is, regular blood transfusions and chelation therapy (Gambari, 2010). In view of the fact that gene therapy could be inaccessible to many because of biological/genetic as well as economic constraints (Gambari, 2010), chemical inducers are being extensively studied. Hydroxyurea has already been used as HbF inducer in both moderate and severe forms of ÃŽÂ ²-thalassaemia (Testa, 2009). Some of the potential inducers of HbF are histone deacetylase inhibitors, DNA-binding drugs and inhibitors of the mammalian target of rapamycin or mTOR pathway (Gambari and Fibach, 2007). Also, according to Gambari and Fibach (2007) chemical inducers need to be used with caution since many of those used so far were potentially cytotoxic. Accelerated apoptosis has been observed in the erythroid progenitors of patients with ÃŽÂ ²-thalassaemia major (Silva et al., 1996). The hormone erythropoietin (Epo), which is the principal regulator of red blood cell production, is known to interact with high-affinity receptors on the surface of erythroid progenitor cells and promote cell viability. Epo has been shown to repress apoptosis via Bcl-XL and Bcl-2 during proliferation and differentiation of erythroid progenitors (Silva et al., 1996). Hence, recombinant human erythropoietin (rHuEpo) could have potential application in the treatment of transfusion-dependent thalassaemia patients as it promotes the differentiation and proliferation of erythroid cells, and stimulates the production of HbF (Makis et al., 2001). 7. Conclusion Inherited haemoglobinopathies including sickle cell disease and thalassaemias result from genetic abnormalities in the synthesis of globin protein chains. Sickle cell disease (SCD) is caused by structural defects in the haemoglobin molecule while thalassaemias occur due to reduced or absent globin chain. Only bone marrow or haematopoietic stem cell transplantation can cure patients with either disease. Clinical management of SCD generally involves supportive therapy consisting of pain relief, fluids and antibiotics, and folic acid supplements. Red cell transfusion is currently a well accepted therapy for clinical management of inherited haemoglobinopathies including SCD and the thalassaemias. Intermittent red cell transfusion is administered to most patients, pre-surgery and in specific cases of severe complications. Persons with severe complications such as stroke, acute chest syndrome or frequent painful sickling crises are treated with hydroxyurea. The only cure available currently for ÃŽÂ ²-thalassaemia major is haematopoietic stem cell transplantation from a compatible donor. Most thalassaemia patients require regular transfusions of red cells and all patients need iron chelation therapy to overcome iron overload. References Adams, R., 2003. Haemoglobinopathies. Haematology (Am Soc Haematol Educ Program) pp.14-39. Adams, R., McKie, V., Brambilla D, et al., 1998. Stroke prevention trial in sickle cell Anaemia. Control Clin Trials 19, pp.110- 129. Andrews, N.C., 1999. Disorders of iron metabolism. N Engl J Med, 341, pp.1986-1995. Andrews, N.C., 2008. Forging a field: the golden age of iron biology. Blood, 112(2), pp.219-230. Anstey, N.M., Russel, B., Yeo, T.W., et al., 2009. The pathophysiology of vivax malaria. Trends Parasitol., 25(5), pp.220-227. Aul, C., Bowen, D.T. Yoshida, Y., 1998. Pathogenesis, etiology, and epidemiology of myelodysplastic syndromes. Haematologica, 83(1), pp. 71-86. Ballas, S.K., 1998. Sickle cell disease: clinical management. Baillieres Clinical   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   Haematology, 11 (1), pp.185-214. Ballas, S.K., 2002. Sickle cell anaemia: progress in pathogenesis and treatment. Drugs, 62(8), pp.1143-1172. Bertero, M.T. Caligaris-Cappio, F., 1997. Anemia of chronic disorders in systemic autoimmune disease. Haematologica, 82(3), pp.375-81. Bessman, J.D., Gilmer, P.R. Gardner, F.H., 1983. Improved classification of anemias by MCV and RDW. Am J Clin Pathol 80, pp.322-326. Beutler, E., Gelbart, T., Lee, P., et al., 2000. Molecular characterisation of a case of Atransferrinemia. Blood, 96, pp.4071-4074. Beutler, E. Waalen, J., 2006. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration?. Blood, 107(5), pp. 1747-1750. Bottomley, S.S., 2006. Congenital sideroblastic anemias. Curr Hematol Rep., 5(1), 41-49. Bunn H.F., 1997. Pathogenesis and treatment of sickle cell disease. N Engl Med.,337(11), pp.762-769. Castro, O., 1996. Systemic fat embolism and pulmonary hypertension in sickle cell Disease. Hematol Oncol Clin North Am. 10(6), pp.1289-1303. Centis, F., Tabellini, L., Lucarelli, G., et al., 2000. The importance of erythroid expansion in determining the extent of apoptosis in erythroid precursors in patients with beta- thalassaemia major. Blood, 96, pp.3624-3629. Chulilla, J.A.M., ColÃÆ' ¡s, M.S.R. MartÃÆ' ­n, M.G., 2009. Classification of anemia for Gastroenterologists. World J Gastroenterol. 15(37), pp.4627-4637. Claster, S. Vichinsky, E.P., 2003. Managing sickle cell disease. BMJ,327, pp.1151- 1155. Cohen, A.R., 1987. Management of iron overload in the paediatric patient. Haematol   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   Oncol Clin North Am., pp. 521-544. Connes, P., Hue, O., Tripette, J., et al., 2008. Blood rheology abnormalities and vascular   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   cell adhesion mechanisms in sickle cell trait carriers during exercise. Clinical   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   Hemorheology Microcirculation, 39(1-4), pp. 179-184. Creary, M., Williamson, D., Kulkarni, R., 2007. Sickle cell disease: current activities, public health implications, and future directions. J Womens Health, 16(5),575-582. Distenfeld, A. Woermann, U., 2009. Sickle Cell Anemia. Accessed 15 February 2010 https://emedicine.medscape.com/article/205926-overview. Dugdale, D.C., 2008. Megaloblastic anemia. Medline Plus, Accessed 28 Jan 2010  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   https://www.nlm.nih.gov/medlineplus/ency/article/000567.htm Engle, M.A., Erlandson, M. Smith, C.H., 1964. Late cardiac complications of chronic, severe, refractory anaemia with haemochromatosis. Circulation, 30, pp.698-705. Fleming, M.D., 2002. The genetics of inherited sideroblastic anemias. Semin Hematol.    39, pp.270-281. Gambari, R., 2010. Foetal haemoglobin inducers and thalassaemia: novel achievements. Blood Transfus. 8(1), pp. 5-7. Gambari, R. Fibach, E., 2007. Medicinal chemistry of foetal haemoglobin inducers for treatment of beta-thalassaemia. Curr Med Chem.14, pp.199-212. Gaziev J, Sodani P Lucarelli C, 2008, Haematopoietic stem cell transplantation in thalassaemia, Bone Marrow Transplantation, 42, S41. Gilman, J.G. Huisman, T.H.J., 1985. A sequence variation associated with elevated foetal GÃŽÂ ³globin production. Blood, 66, pp.783-787. Gladwin, M.T. Kato, G.J., 2005. Cardiopulmonary complications of sickle cell disease: role of nitric oxide and hemolytic anemia. Haematology (Am Soc Hematol Educ   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   Program), pp. 51-57. Goldberg, M.A., Brugnara, C., Dover, G.J. et al., 1990. Treatment of sickle cell anaemia with hydroxyurea and erythropoietin. NEJM, 323(6), pp. 366-372. Haas JD Brownlie T, 2001, Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship, J Nutr., 131(2 Suppl): 676S-690S. Halterman, J.S., Kaczorowski, J.M., Aligne, C.A. et al., 2001. Iron deficiency and cognitive achievement among school-aged children and adolescents in the United States. Pediatrics, 107, pp. 1381-1386.      Hankins J, Jeng M, Harris S, et al., 2005, Chronic transfusion therapy for children with sickle cell disease and recurrent acute chest syndrome, J Paediatr Haematol Oncol 27:158 161. Herrick JB, 1910, Peculiar elongated and sickle-shaped red corpuscles in a case of severe anemia, Arch Intern Med.6:517-521. Hershko C Skikne B, 2009, Pathogenesis and management of iron deficiency anaemia: Emerging role of Celiac disease, Helicobacter pylori, and autoimmune gastritis, Seminars in Hematology, 46 (4): 339-350.Iolascon A, De Falco L. Beaumont C, 2009, Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis, Haematologica 94(3): 395-408. Jison ML, Munson PJ, Barb JJ et al., 2004, Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease, Blood, 104(1): 270-280.   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   Killip S, Bennett JM Chambers MD, 2008, Iron deficiency anemia, American Family Physician, 75(5): 671-678. Kohgo Y, Ikuta K, Ohtake T. et al., 2008, Body iron metabolism and pathophysiology of iron overload, Int J Hematol. 88(1): 7-15. Krantz SB, 1994, Pathogenesis and treatment of the anemia of chronic disease, Am J   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   Med Sci.,307(5): 353-359. the art, Expert Opinion on Biological Therapy, 7(2): 161-172. Josephson CD, Su LL, Hillyer KL, et al., 2007, Transfusion in the Patient With Sickle Cell Disease: A Critical Review of the Literature and Transfusion Guidelines, Transfusion Medicine Reviews, 21(2): 118-133. MakisAC, ChaliasosN, Hatzimichael EC et al., 2001, Recombinant human   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   erythropoietin therapy in a transfusion-dependent ÃŽÂ ²-thalassaemia major patient,   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   Annals of Haematology, 80(8):492-495. Means RT Jr., 1996, Advancement in the anemia of chronic disease: A cytokine- mediated anemia, Stem Cells, 13(1): 32-37. Means RT Jr., 2003, Recent developments in the anemia of chronic disease, Current   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   Hematology Reports, 2(2):116-121. Miller S, Rao S, Dunn K, et al., 1995, Priapism in children with sickle cell disease, J   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   Urol, 154:844- 847. Mims MP, Guan Y, Pospisilova D, et al., 2005, Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload, Blood,105:1337- 1342. MuÃÆ' ±oz M, Villar I GarcÃÆ' ­a-Erce JA, 2009, An update on iron physiology, World J Gastroenterol, 15(37): 4617-4626. Nadkarni A, Gorakshakar AC, Lu CY, et al., 2001, Molecular pathogenesis and clinical variability of ÃŽÂ ²-thalassaemia syndromes among Indians, American Journal of Haematology, 68:75-80. Olivieri NF Brittenham GM, 1997, Iron-chelating therapy and the treatment of   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   thalassaemia, Blood, 89(3): 739-761 Pauling L, Itano HA, Singer SJ, et al., 1949,   Sickle cell anemia: a molecular disease, Science, 110(2865):543-548. Quigley JG, Yang Z, Worthington MT, et al. 2004, Identification of a human heme exporter that is essential for erythropoiesis, Cell, 118:757-766. Ragusa A, Lambardo M, Beldjord C, et al., 1992, Genetic epidemiology of ÃŽÂ ²- thalassaemia in Sicily: do sequences 58 to the GÃŽÂ ³ gene and 58 to the ÃŽÂ ² gene interact to enhance HbF expression in ÃŽÂ ² -thalassemia?, Am J Hematol, 40:199-206. Richardson M, 2007, Microcytic anemia, Pediatrics in Review, 28:5-14. Rifikind S, Waisman J, Thompson R, et al., 1979, RBC exchange pheresis for priapism in sickle cell disease, JAMA, 242:2317 2318. Rodgers GP, Noguchi CT, Schechter AN, 1985, Irreversibly sickled erythrocytes in sickle cell anemia: A quantitative reappraisal, Am J Hematol., 20(1): 17-23. Rodgers GP, Dover GJ, Uyesaka N, et al., 1993, Augmention by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease, NEJM, 328(2): 73- 80. Rosenfeld C List A, 2000, A hypothesis for the pathogenesis of myelodysplastic syndromes: implications for new therapies, Leukemia, 14(1): 2-8. Ru YX, Mao BY, Zhang FK et al., 2009, Invasion of erythroblasts by Plasmodium vivax: A new mechanism contributing to malarial anaemia, Ultrastruct. Pathol., 33(5):236-42.   Shemin, D. Rittenberg D, 1946, The life span of the human red blood cell, J Biol Chem, 166: 627-636. Siah CW, Ombiga J, Adams LA, et al., 2006, Normal iron metabolism and the pathophysiology of iron overload disorders, Clin Biochem Rev. 27:5-16. Silva M, Grillot D, Benito A, et al., 1996, Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. Blood, 88:1576-1582. Sokol RJ, Booker DJ Stamps R, 1992, The pathology of autoimmune haemolytic anaemia, J Clin Pathol., 45: 1047-1052. Spivak, JL, 2002, Iron and the anemia of chronic disease, Oncology, 16(9 Suppl 10):25- 33. Spritz RA Forget BG, 1983, The thalassemias: molecular mechanisms of human genetic disease, Am J Hum Genet., 35:333-361. Steinberg MH Rodgers GP, 2001, Pharmacologic modulation of foetal haemoglobin, Medicine, 80:328-344. Styles LA Vichinsky E, 1994, Effects of a long-term transfusion regimen on sickle cell- related illnesses, J Pediatr., 125:909-911. Tanno T, Bhanu NV, Oneal PA et al., 2007, High levels of GDF15 in thalassemia   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   suppress expression of the iron regulatory protein hepcidin, Nature   Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚  Ãƒâ€šÃ‚   Medicine, 13:1096 1101. Tefferi A, 2003, Anaemia in adults: a contemporary approach to diagnosis, Mayo Clin   Proc.78:1274-1280. Testa U, 2009, Fetal hemoglobin chemical inducers for treatment of   Haemoglobinopathies, Ann Hematol. 88:505-528. Thein SL, 1993, ÃŽÂ ²- Thalassaemia. In: Higgs DR Weatherall DA, editors, Baillieres clinical haematology: the hemoglobinopathis, Vol 6, Bailliere Tindall, London, p151-175. Tischkowitz MD Hodgson SV, 2003, Fanconi anaemia, J Med Genet 2003;40:1-10 doi:10.1136/jmg.40.1.1 Tuck S, James C, Brewster E, et al., 1987, Prophylactic blood transfusions in maternal sickle cell syndromes, Br J Obstet Gynaecol., 94:121 125. Walter PB, Harmatz P Vichinsky E, 2009, Iron metabolism and iron chelation in sickle cell disease, Acta Haematol., 122(2-3):174-183. Weatherall DJ, 1969, The genetics of the thalassaemias, British Medical Bulletin, 25(1): 24-29. Weatherall DJ, 1996, The molecular basis for phenotypic variability of the common thalassaemias, Mol Med Today 1:15-20.   Weatherall DJ, 1997a, ABC of clinical haematology. The hereditary anaemias, BMJ 314:492-496. Weatherall DJ, 1997b, Fortnightly review: the thalassaemias, BMJ, 314(7095):1675- 1678. WHO (1968), Nutritional anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser. 1968;405:5-37. Wun T, 2001, The role of inflammation and leukocytes in the pathogenesis of sickle cell disease, Hematology, 5(5): 403-412.

The Dangers Of Early Sexual Activities - 848 Words

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Henry James And The Beast In T free essay sample

Essay, Research Paper The Beast in the Jungle is a narrative that expresses tragic sarcasm and great loss. Henry James commences his narrative by presenting two characters: John Marcher and May Bartram. The two meet at a sign of the zodiac, after a ten-year separation. The sign of the zodiac is filled with effete art, old-timers, and other invaluable objects. John notices May ab initio, and he immediately senses a deep but misplace connexion towards her. They eventually engage in conversation and right off May knows precisely who John is, although John still can t topographic point where he knows May. She reminds him about how and who introduced them to each other in Europe. May startles John, when she asks him if his compulsion with a hereafter calamity had come into realisation. John, of course, is wholly taken back by such an intimate inquiry. He had forgotten that he shared a really intimate secret of his with May. We will write a custom essay sample on Henry James And The Beast In T or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page He has lived his life consumed, waiting for a hideous catastrophe to happen. John invites May to wait and watch with him ( May being the lone individual who understands him ) ; she accepts. John and May # 8217 ; s friendship shortly flowers, and May attains a London flat to be closer to John. It is neer made clear if whether this is merely a friendly relationship or a romantic relationship. Regardless, old ages pass and shortly they are old. May is diagnosed with a rare blood disease, which will stop her life. John is grief stricken when he hearsthe intelligence B Greenwich Mean Time he can’t aid but experience that May is maintaining a secret about his oncoming catastrophe. When May dies, all of the replies John was trusting she could reply dice with her. John sinks into a depression and takes a twelvemonth long trip around the universe. When he returns to England, he visits the May’s resting topographic point. As he stares at May’s gravestone, John begins to recognize that he was profoundly in love with May. Because of his compulsion with this â€Å"disaster† he was unable to acknowledge this love. He realizes that this animal which sprang into his life, this catastrophe he waited for, was really his beloved’s decease. He realizes his errors and declinations non populating his life to its fullest. He was so consumed by his compulsion with calamity that his greatest error was losing the one thing that affair most. John, in the terminal, is entirely. II. The chief subject or theory in James # 8217 ; # 8220 ; Beast in the Jungle # 8221 ; is that life and love are non to be taken for granted. When we live merely within ourselves, non sharing, non showing our feelings, we become empty and sad persons. Because John was populating in changeless fright, he neer allowed himself to populate and to love. When he realizes that May was the greatest thing he of all time had, and neer told her so, John regrets his errors. I assume James # 8217 ; is seeking to state us that showing and taking a opportunity is necessary, for a life of sorrow is the most painful but yet the preventable result.

The Beginning Of World War II Essays - International Relations

The Beginning of World War II At daybreak on the first day of September, 1939, the residents of Poland awakened to grave news. A juggernaut force of tanks, guns, and countless grey-clad soldiers from nearby Germany had torn across the countryside and were making a total invasion of the Pole's homelands. Germany's actions on that fateful morning ignited a conflict that would spread like a wildfire, engulfing the entire globe in a great world war. This scenario is many people's conception of how World War II came about. In reality, the whole story is far more detailed and complex. The origins of war can be traced as far back as the end of the first World War in 1919, when the Treaty of Versailles placed responsibility for that terrible war squarely on Germany. Years later, in the Far East, Japanese ambition for territory led the nation to invade Manchuria and other parts of nearby China, causing hostilities to flare in the Pacific Rim. Great Britain, the United States, and many other nations of the world would all be drawn into battle in the years to come, and each nation had it's own reason for lending a hand in the struggle. Although Germany was the major player in World War II, the seeds of war had already been planted in the Far East years before conflict in Europe. On September 18, 1931, the powerful Japanese military forces began an invasion of the region known as Manchuria, an area belonging to mainland China. This action broke non-aggression treaties that had been signed earlier. It also was carried out by Japanese generals without the consent of the Japanese government. In spite of this, no one was ever punished for the actions. Soon after the assault on China, the Japanese government decided it had no choice but to support the occupation of Manchuria. By the next year the region had been completely cut off from China (Ienaga 60-64). Because of the Japanese offensive in China, the League of Nations held a vote in October to force Japan out of the captured territory. The vote was passed, 13 to 1, but Japan remained in control of Manchuria. A second vote, taken in February, 1933, a formal disapproval of the Japanese occupation, was passed 42 to 1. Instead of expelling Japan from the area of Manchuria, it caused the nation to formally withdraw it's membership in the League of Nations the next month (Ienaga 66). Now unrestrained by the recommendations of the League of Nations, Japan continued it's intrusion onto Chinese soil. By 1937 Japan had moved military forces into Beijing, Shanghai, and Nanjing, as well as other regions of China. By 1940, Japanese seizure of territory had spread to deep inside Southeast Asia and even parts of Australia (Sutel et al). Also in 1940, the Triparte Pact was signed, allying Japan, Germany, and Italy into a powerful force that stretched halfway around the planet. The association with Hitler and Germany unified the war in the Pacific and the war in Europe. Japan was now fully involved in what came to be known as World War II. As warfare raged in the Pacific Rim, a chain of events was unfolding that would produce catastrophic results. The Treaty of Versailles of 1919 held Germany fully accountable for the tragedy of World War I. The nation was stripped of large areas of land, it's armaments, as well as it's dignity. In addition, the reparations that were to be paid to the allied nations virtually destroyed the economy of Germany. The resentment of the treaty burned in the hearts and minds of Germans for years afterward. In 1933, a man by the name of Adolf Hitler was elected Chancellor of Germany after working his way up the ladder of government. By speaking against the Treaty of Versailles and making promises of a better life to the German people, Hitler gained the support of his fellow countrymen, and he easily won the election. Almost immediately after Hitler took office he began securing his position in power. Hitler took steps to eliminate all opposition, including political parties and anyone else who spoke out against him. The death of President Hindenburg in 1934

First mover, last mover free essay sample

The first mover theory refers to the competitive advantage a company earns by being the first to enter a specific market or industry. With this movement comes advantages and disadvantages. An advantage of being a first mover is the technological advantage through sustainable leadership in technology. If the firm is the first one to introduce the technology, it reaps the benefits of selling those products to consumers. It also leads the way with research and development and obtaining patents for its products. This advantage can also create barriers to entry, as few firms can compete profitably. A first mover may also be able to obtain scarce assets. The first mover gains control of the assets that already exist. If the firm has superior information, it may be able to purchase assets at market prices below those that come later in the evolution of the market. Again, the acquisition of scarce resources may limit the number of firms that can compete in the market. We will write a custom essay sample on First mover, last mover or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page Being a first mover means paying less buyer switching costs that may arise from new suppliers, new software or computers, and training employees for new protocol or software. Late entrants have to pay more for these switching costs. Switching costs typically enhance the value of market share obtained early in the evolution of a new market. With being a first mover, a company does not have to compete with as many established products as a last mover. Being early into a market means that competition is not as fierce and the company can set industry standards and gain market share easier than if it was competing with firms already established in the industry. No brand reputation has been formed yet as well. With being a first mover come disadvantages as well. One of these disadvantages is late movers being ‘free-riders’ on the first movers investments in areas such as research and development and other areas. Late movers can also exploit employee screening and tap into skilled labor at a lower cost because the first movers have given the employees experience and  training. In a market with considerable uncertainty, being a late mover means some of the uncertainty is relinquished before the firm enters the market. The automobile and aircraft markets are examples of this. Late movers can jump into the market once it has been established and know that there is little uncertainty that it is going to be a profitable industry. Once uncertainty is resolved, competition shifts to price, so those with low manufacturing costs have a competitive advantage. Being a first mover means new technology is brought to consumers earlier, but late movers can exploit technological discontinuities to displace incumbents. It may be difficult for first movers to see that last movers are displacing their technology as the new technology appears while the old technology is still growing. The late movers can basically take advantage of the early technology and make improvements on it. Finally, a disadvantage of being a first mover is incumbent inertia. This means that the first mover firms may be locked in to fixed assets, may be reluctant to get rid of existing product lines, or be organizationally inflexible. Firms may want to ‘harvest’ sunk costs such as buildings or marketing channels, instead of drastically changing itself to adapt to the market. Being a last mover means entering a market after it has been established by the first movers. There are advantages and disadvantages to being a last mover that are directly related to the advantages and disadvantages of a first mover. Firstly, being a last mover means the company knows how the product has been perceived and knows that the uncertainty of the market has been eliminated. Research and development costs will be less because the first movers have done extensive research to produce products. The last movers can piggy-back off this RD make improvements to the products already established. Last movers can take advantage of trained personnel from first movers. The first movers can train employees and give them experience, and then the last movers can come in and take them away, utilizing their skills. They may have to pay a higher salary to pull them away from the first mover, but they will save money on training. Finally, being a last mover means switching costs are lower. This is related to the idea that the market is already established. Since last movers can see where the market is headed, it can invest in these assets instead of switching old assets over to the new assets. This will ultimately save the company extensively. There are disadvantages to being a last mover as well. One of these disadvantages is possibly missing a opportunity to enter a market altogether. The market may disappear altogether before the firm can really establish itself. Assets that were used to enter the market will be obsolete. Another disadvantage is less potential customers because the market is flooded with first and last movers. Other companies may have the same idea to enter the market late, and with all the different companies competing in the same market, this may cause too many similar products to be on the market. This can lead to companies not being able to differentiate themselves. Last movers may not be able to keep up with technological advancements because they have not been established very long. Their RD departments need time to make technological improvements and since they are not in the market for long, may fall behind the first movers in this area. A final disadvantage of last movers is being labeled a â€Å"copycat† or â€Å"imitator.† When a late mover enters the market, since they are competing with established products, consumers may think they are just copying their ideas and turn away from their products. It is imperative that the new products established differences so that consumers see that there is a  benefit to choosing the new product. There are several examples of firms that are first movers that have been successful and unsuccessful. The obvious first mover example is Apple, which introduced products such as the iPad and iPhone. Other examples are IBM, which introduced the first 16 bit personal computer, GM in the car industry, and Yahoo, the first online search site. There are also examples of unsuccessful late movers. An example is AOL, which led the way with dial-up internet but later was replaced with DSL and cable internet. Other examples are Napster, which ran into legal issues, Motorola, and Wal-Mart as a low cost products provider. Some examples are last mover firms that have been successful are Facebook as a social media site, Home Depot for home improvement products, Netflix for online movies, and Samsung in the phone industry. All these firms entered their respective industries late but have established a competitive advantage that makes them viable in each industry.

Hcs 405 Healthcare Financial Accouting Essays

Hcs 405 Healthcare Financial Accouting Essays Hcs 405 Healthcare Financial Accouting Essay Hcs 405 Healthcare Financial Accouting Essay In the United States, organizations are financially accessible because of many years of financing cuts, reductions in Medicare payments imposed by Balanced Act of 1997, decreases in Medicaid reimbursements, and the lowering stresses of controlled care (University of Phoenix, 2013). Organizations and other health care facilities should organize cautiously when the situation comes to financing choices, service agreements, type of equipment, physician favorites, and locating to assist in making the best decisions.According to several published and quoted surveys, organizations are postponing or eliminating equipment investments in short-term (Barlow, 2009). Leasing is a substitution to another means of financing. When an organization is deciding when to lease or purchase, the team will decide by how much cash they own from their current funds. If the organization does not have the funds to purchase equipment, then the organization will borrow money to purchase the equipment. Service agreements are contracts to examine or repair the equipment and can be made part of a lease settlement.Whether the equipment is leased or bought, a service agreement will be indicated as an expense and does not need to be used for comparison between leasing and purchasing (Baker amp; Baker, 2011). Elijah Heart Center is a 120,000 square foot hospital to manage, and function as a coronary care unit for up to 140-beds in New York. The finance department has reported that Elijah Heart Center is facing a potential working capital shortfall because of discounts given to manage care companies, decreased in Medicare reimbursements, increase in present liabilities, unused equipment placed in patient’s room, and obtain the workflow of contract nurses.Elijah Heart Center will receive 2,300,000 from Medicare and other administered care organizations within three months but is required to set a cost saving target of 900,000 for the first year (University of Phoenix, 2013). The cost cutting options for Elijah are downsizing staff, cutting benefits, reducing agency staff, decreasing length of stay, and modifying the skill mix. Downsizing staff and cutting their benefits greatly would impact the quality of care and potentially would cause staff to obtain excessive amount of overtime. Reducing a patient’s length of stay would not affect the annual savings for the organization.Reducing high waged agency staff would increase the savings by 2,043,683 and changing the skill mix would increase the savings by 1,471,452 (University of Phoenix, 2013). Reducing the agency staff will increase savings because the organization will save on the premiums and management fees. Over a period of time, changing the skill mix will allow employees to assist with easy task and others personal to focus on their necessary tasks. Option one loan was the best choice for maintain beneficial cash flow because there was not a prepayment limitation.Therefore, the organization could pay the loan off within three months from the payments from Medicare and managed care organizations (University of Phoenix, 2013). Elijah Heart Center needs to choose to buy or refurbish radiology equipment because the patient volumes are increasing and equipment is aging. The useful life of a CT scanner is considered to last for approximately 10 years. An x-ray machine useful life is 15 years with a low change of technological advancements. An ultrasound system is considered to last five years, but with a high continuing advancement of technology (University of Phoenix, 2013).The best loan choice for the high-speed CT scanner is the refurbish loan because they can use the CT scanner for to the end of the useful life and then upgrade. An operating lease will have to pay for an upgrade fee after three years (University of Phoenix, 2013). Purchasing health care equipment indicates acquiring the title or undertaking ownership of the product, which is documented on an organization’s balance sheet. The organization could purchase the equipment by disbursing cash from the company’s money funds, or the organization could finance the entire or a portion of the purchase.When financing happens, the resultant obligation is documented on the organiza tion’s balance sheet (Baker amp; Baker, 2011). The best loan choice for the x-ray machine is a capital lease because the payment of present value is higher compared to taking an operating lease or buying refurbished equipment. The capital lease option does not cover the care of technology advancements but the useful life is 15 years and with the bargain price of the x-ray machine is the best option (University of Phoenix, 2013). The organization could lease to purchase, which is an agreement to contract o purchase. The equipment is still documented on the balance sheet as an asset with a corresponding liability is called capitalizing (Baker, amp; Baker, 2011). The best loan choice for the ultrasound machine is the operating lease, because it has lower upfront payment and lower monthly installments. With the operating lease, the organization will confirm on receiving the newest technology (University of Phoenix, 2013). An operating lease is counted as an operating expenditure that will be indicated as a cost, but is not capitalized or documented on the balance sheet.An operating lease is considered as a cost of present operations, whereas a financial lease is considered as an asset and an obligation. The operating lease develops into an operating expense by a payment that is made within that time interval (Baker, amp; Baker, 2011). Elijah Heart Center is need of a $75 million expansion and advancement project with the increasing number of patients. The organization will house five open-hear operating rooms, twenty critical cardiac patient rooms, and seven cardiac catheterization labs, along with the newest cardiac technology.After considering the net present value, collateral requirements, cost for funding, and prepayment limitations, the best funding option for the four-year planned expansion is the HUD 242 loan insurance program. The HUD 242 loan insurance program qualifies hospitals to have their debt financed as an investment category, which arranges the lowest borrowing prices available. An advantage of this bond is that they are capable to be redeemed after eight years, so the organization could purchase the bonds again and redistribute the debt at a lower price (University of Phoenix, 2013).In conclusion, understanding the difference between purchasing new equipment, purchasing refurbish equipment, and leasing equipment is an intelligent financial requirement. Always, considering the impact of the financial decisions will affect the organization’s cash flow and balance sheet. Deciding on the most cost-effective loan depends on the interest rate, prepayment limitations, net present value, and the usefulness of life. Knowledge and comprehending the terms of agreement will assist in future, strategic investments within an organization.These financial accounting concepts are essential for implementing the tactics to succeed operative organization outcomes. References Baker, J. J. , amp; Baker, R. W. (2011). Health care fi nance: Basic tools for nonfinancial managers (3rd ed. ). Jones amp; Bartlett. Barlow, R. (2009). Effective equipment planning begins in the basement. . Healthcare Purchasing News, 33(9), 50-52. University of Phoenix. (2013). Analyzing Financial Indicators for Decision Making [Multimedia]. Retrieved from University of Phoenix, HCS 405 Health Care Financial Accounting website.

Bacterium Capsule Research Proposal Example | Topics and Well Written Essays - 500 words

Bacterium Capsule - Research Proposal Example It is a layer that lies outside the cell wall of bacteria, it is well organized and it is not easily washed off. This makes it diffuse through the tracheal system. Its slime layer diffuses into the surrounding medium as a loosen-demarcated secretion. The capsule usually consists of polysaccharides and is water soluble thus dissolves in the moisturize tracheae through the spiracles. Thus they are difficult to stain using standard stains as they do not adhere to the capsule (Chapman, 2004). Since the capsule remains pale and colorless, it is difficult to be detected and appears as a ring around the cell. The tracheae are water filled as they consist of a permeable membrane of the surrounding tissues which make the capsule soluble since it is water soluble. The water level, however, retracts due to the increase in the concentration of lactic acid found in the muscle cells during the respiration system. The capsule contains external chemical sensors which therefore detects the concentration of lactic acid, lowering the water potential in the system which is then drawn back into the cells through osmosis process while the capsule gets closer to the muscle cells. While the diffusion pathway is reduced as a result, the capsule can then be transferred more easily through the tracheal. The bacterium capsule is typically stimulated for easy movement throughout the system. The neurosecretory cells made in the cell body consist of the prothoracic gland which acts as circulatory s ystem storage gland and hormonal control of insect molting (Ulrich, 2009).

Appeal admission letter to ucsd Essay Example | Topics and Well Written Essays - 500 words

Appeal admission letter to ucsd - Essay Example I play tennis in the Tennis Junior Varsity Team. I play the saxophone in the Marching Band and the violin in the Orchestra. As you will have noticed, I am not only a dedicated and responsible person in my academic work, but I am also a musician, an athlete, involved in community work, and I am environmentally versed and active. This is the reason why I am applying to UCSD. Having an Environmental Science major, a Marching Band, an Orchestra, and tennis teams will give me the opportunity to continue to excel in those areas that I am already active in and it will help me to achieve my goals and objectives by being part of your campus. I am a studious person. I start and finish tasks before or on their due dates. I work independently and as a team member. I have assumed leadership roles. I am multi-tasks disciplined and I am successful being involved in all of my tasks. I would like to be involved in assisting your faculty that is conducting research in any of these areas: global warming; shortage of power; and/or, environmental pollution. I hope that the University of California in San Diego sees in me as a successful student that will fulfill his/her (identify your gender) baccalaureate. I hope that you give me the opportunity to become part of your alumni association as my

Multinational competitin and Corporate Social Responsibility analysis Essay - 1

Multinational competitin and Corporate Social Responsibility analysis of Burberry - Essay Example The design, development, production and selling of the products of the company are all based in United Kingdom. However, the fabric and other material for the manufacturing of the products are done on the company own facilities in United Kingdom (Burberry, 2015a; Reuters, 2015). At present the international, apparel, accessories market and market for luxury goods have shown a low growth from the 2007 to the year 200, but from the year 2010 the entire market has witnessed some acceleration and reached up to moderate growth and predictions said that the market is expected to be stable by the end of 2016. The total revenue of the apparel, accessories and luxury goods global market is expected around 1,778.5 billion for the year 2011. The figures represent a 3% CAGR (compound annual growth rate). The report also revealed that the sale of the apparels is the most lucrative one in the global market of apparel, accessories and luxury goods in the year 2011 and it has captured the 66.1% of the overall value of the market in terms of revenue. In this perspective, the market performance is forecasted to accelerate in coming five years with an expected compound annual growth rate of 3.9% and with such percentage the market value is driven to reach the level of 2155.1 billion by the end of the year 2016. When it comes to Burberry, the focus of the company is towards several different segments in the population but the theme of the company is same that is, it is inclined toward functional luxury. Burberry foes not only serve to the young and adults but also the company has good range luxurious products for kids. At present the main focus of the company is three main regions. The Asia Pacific region represent the 39% of wholesale and retail revenue, the European, African and Middle Eastern region along with India (EMEIA) hold 36% of the revenues where as the contribution of America is 25% in the total revenue of Burberry

Is Free Trade Possible?

Is Free Trade Possible? Tom Hobson ‘Free trade is neither possible nor desirable.’ Do you agree with this Statement? Roger Scruton makes the claim free trade is neither possible nor desirable in A Political Philosophy and takes a conservative political viewpoint in defence of national sovereignty (2006). Taking the statement within the realm of international political economy it draws in the debate of the role of the World Trade Organisation (WTO) in advancing free trade as its aim, the economic debate between those who advocate free trade from Adam Smith and David Ricardo and their modern advocates and those who oppose it including Joseph Stiglitz and an analysis of the power relations that entail in free trade negotiations as well as the consequences answering first whether it is possible and secondly its degree of desirability. Free trade in a majority of production areas and scenarios is possible but its desirability is the key debate, the domestic consequences for both developing and developed states can distort national economies in a globalised world. It is a complex issue that is largely ap proached through the WTO. Free trade has an impact on developmentalism for industrialising countries and is connected to hegemonic theories of world governance to uphold the system. Free trade is a possible concept for a globalised world but it is largely undesirable when considering the human impact of market forces. Krasner argues that a hegemon is required for a global system of free trade to be viable, the essential principle is that the distribution of power amongst states dictates the international economic system. He highlighted the role of Britain during the 19th century and the US post World War One and marked the decline in power of the US up to the 1970s being the precursor to the end of a liberal international free trade system. According to Krasner only an open hegemon has the sufficient power to provide the public goods and any other system is inherently unstable (Krasner Webb, 1989, pp.183-184). But in the contemporary international political economy with the rise of China economically and militarily alongside the supremacy of the US there are infact increases to the global liberalisation movement (Chestnut Johnston, 2009, pp.252-253). Hegemonic stability theory has a place in contemporary international political economy but it is not overriding. The realist hegemonic stability theory is very rigid for a free trade international system and empirical evidence shows it is true that a hegemon can meet the public goods cost without jeopardising its own state security it isn’t necessarily the only situation where free trade stemming from state power can flourish as we can see with the rising bipolar international system including China. Krasner’s theory concentrates on the Cold War era and how far the US was willing to open world trade at its own expense in order to have an advantage over the Soviet Union in absolute power (Krasner Webb, 1989, p.196). The state power relationship that Krasner offers for open trade in the global system is very convincing in terms of state security and his realist perspective of the international political economy is as a part of international relations rather than separate. It shows that contrary to Scruton’s statement that free trade is possible within a system whereby public goods are met by a state or states are able to meet the demand without risk to their own security. But a more technical approach taken by Richard Baldwin on regionalism and its problems show that international trade is inhibited by the numerous regional rules and argues that a multilateralisation of the existing systems will be required for a truly global free trade system (Baldwin, 2006, p.1451). Two of the issues he analyses are the current asymmetric negotiations whereby nations and interest groups seek to minimise losses rather than maximise gains and race to the bottom tax competition unilateral negotiations as an alternative to regionalism and mulitlateralism which leads to fragmentation in the supply chain (Ibid, 2006, pp.1469-1471). A good example of asymmetric negotiations can be seen between the US and China on tyres in 2009. The Interest groups of labour including United Steel and Allied Industrial and Service Workers International Union pushed US negotiations to introduce tariffs on Chinese imports of tyres on the premise of saving US jobs and manufacturing (i.e. minim ising losses). The result of US imposition of tariffs argued by Ilkensen is a cost to the consumer of $600-700 million annually which results in a cost of $300,000 annually per job saved (Ilkensen, 2009). This follows Baldwin’s argument that unilateral and asymmetric trade negotiations lead to strength in interest groups and poor outcomes. It is also an example of Barry Eichengreen’s perspective on the role interest groups have on limiting policy of free trade with reference to the Smoot-Hawley tariffs of the 1930s, the movement towards protectionism by domestic pressure groups (Eichengreen, 2003, p.59). the strength of institutions beyond the state in affecting the outcomes of trade negotiations are able to prevent the posibility of free trade in the international political economy as this example and Eichengreen highlight. Further to this the position of Richard Baldwin on the strength of regionalism in forcing such action as well as inhibiting the prospect of global international free trade by having a multitude of incompatible rules and aims. The possibility of free trade is disputed; the broad theory of Krasner would indicate that it is possible but the specifics of unilateral trade and regionalism show the limits of global free trade. Turning to whether free trade is desirable concentrates on the WTO and the effects of free trade. The comparative advantage of Smith and Ricardo according to Ilkensen applies in the supply chain of the globalised modern political economy because it is how countries ascend or descend the chain, liberalisation of trade restrictions allows producers to serve the global supply chain in specific areas of comparative advantage. He uses the example of the Ipod with highly skilled engineers in Californa and low wage manual workers in China maintain low costs so that consumer prices are not high and members of the labour force can be freed to work in other sectors (Ilkensen,2009, pp.10-15). His argument rejects the idea of international trade being a zero sum game that is assumed by the critics of free trade, his emphasis is on productivity to create growth. The central argument is that all consumers benefit from free trade and the emphasis of the entire argument should shift from producers to consumers (Ibid 2009 pp.10-15). Ilkensen’s analysis of a global supply chain also rejects the premise of a global north/south divide and he argues that there is not national competition but global cooperation (Ibid, p.4). Similarly, the mutual reduction of tariffs ends the prisoner’s dilemma that ends in a Nash equilibrium that satisfies neither party and as argued by Subramanian the developed nations in the WTO system have reduced their tariffs the most while allowing the rest to maintain protection of 2/3 of their imports (2007, pp. 152-154). Ilkensen’s argument ignores many aspects of international political economy and purely concentrates on the economics of the process of free trade. The rejection of the orthodoxy on primacy of producers over consumers is a very market based approach that concludes it is positive for all involved and a desirable outcome of trade negotiations particularly when you highlight that developed nations are seen to give greater concessions. The WTO is an advanced and technical, monitoring and compliance mechanism for managing trade relations where tackling asymmetric power is the key to its existence where every member is given equal standing and access to the Dispute Settlement Understanding (Lanoszka, 2009, pp 47-51). Contrasting the view of Ilkensen are the criticisms placed against the WTO. Sarah Joseph highlights the dependency theory of Singer-Prebisch where free trade deepens the international division of labour that does not work in long term development because it entrenches positions of nations within the core industrialised west, the semi-periphery and periphery of developing nations (2013, p.8). This marxist interpretation of the international political economic system emphasises the asymmetric trade negotiations forced upon developing nations by the WTO to ensure the west’s supremacy in terms of international relations and economics. She argues that with it being in the developed world’s inter est to ensure a lack of diversity in the economies of the developing nations to create an underclass of labour that relies on manufactured imports and foreign direct investment (Ibid, p.9). She accuses the WTO of serving goods and services of big business rather than individuals; in particular that of the Trade-Related Aspects of Intellectual Property Rights (TRIPS) for creating worldwide patents on drugs which therefore prevents their mas use across developing nations to tackle health issues (Ibid, pp. 285-287). Joseph’s critical analysis of the effect of the WTO in pushing for free trade highlights the dominance of the west in maintaining the status quo and not creating the development it promises. In this the problems of free trade show that it is not universally desirable as an economic system. Similarly Joseph Stiglitz attacks the system of free trade for preventing development in the poorest nations by forcing them to state infrastructure and industry. Stiglitz agrees with Scruton’s argument that liberalisation and international economics need to be sensitive to national economies in order to ensure growth and progress; he argues that free trade is about efficiency nations rather than growth, comparative advantage assumes full employment, stability in developing countries’ and uses the example of Southeast Asia where high investment in physical and human activity acted as catalysts for growth (Stiglitz Charlton, 2007, p. 15-25). For developing countries protection of infant industries is more often than not optimal because foreign investment is dependent on selling at a loss until productivity rises which will not happen and in terms of state building the easiest form of revenue is import tariffs and the priorities of a developing economy are not in efficie ncy but growth (Ibid, 2007, pp.32-29). The argument of Stiglitz takes a different perspective on the aims of developing nations from efficiency to growth in their own context; developing nations have very different needs to those that are developed in terms of human development. He highlights the fact that free trade only benefits developed nations that force liberalisation on other nations through the WTO (Ibid, 2007). A further argument against free trade can be found in the environmental lobby that sees potentially global economic expansion as ‘inimical to the goal of preserving a clean, healthy, and sustainable global commons’ (Grossman Krueger, 1991, p.2). The analysis of the report by Grossman and Krueger was specifically regarding the NAFTA trade agreement and the environmental impact on Mexico. Specifically it highlights the problem with Mexico being a relatively poorly developed nation that should industrialisation occur due to liberalisation then pollution will grow under an undeveloped regulatory framework (Ibid, pp.3-4). But the Kuznets curve refutes the basic assumption of the report that economic growth leads to exponential environmental degradation by concluding that the greater the GDP per capita the lower the overall pollution in the long term (Stern, et al., 1996, p.1159). Free trade has initial environmental degradation but the long term forecasts of the Kuznets curv e negate the argument against free trade as a desirable system of international economics. The possibility of free trade is a debated topic and though the technical approach of Baldwin argues that global free trade isn’t a possibility with the complexities of regionalism the overarching argument of Krasner that a hegemon, or as argued more recently a number of nations, providing public goods to fulfill the global demand without incurring too great a cost is a convincing argument in the contemporary international political economy that free trade is possible. But the key debate is whether free trade is desirable in a global context. Taking international economics as a global supply chain then Ilkensen’s argument that the comparative advantage of each country placed within this chain then free trade is necessary to lead to the most efficient forms of growth and all benefit. But the arguments of Stiglitz, Charlton and Joseph emphasis the underlying principle that global trade is a zero-sum system that embeds the current and historical inequalities between the gl obal north and south. To conclude on whether free trade is desirable is dependent on whether the aim is growth or effieciency; growth that it is unfair to developing nations, efficiency that it benefits all. It is too complex a subject to conclude either way in this essay whether it is desirable. Bibliography Baldwin, R., 2006. Multilateralising Regionalism: Spaghetti Bowls as Building Blocs on the Path to Global Free Trade. The World Economy, 29(11), pp. 1451-1518. Chestnut, S. Johnston, A. I., 2009. Is China Rising?. In: E. Paus, P. Prime J. Western, eds. Is China Changing the Rules of the Game. NY: Palgrave Macmillan, pp. 237-260. Eichengreen, B., 2003. The Political Economy of the Smoot-Hawley Tariff. In: J. Frieden D. Lake, eds. International Political Economy: Perspectives on Global Wealth and Power. London: Taylor Francis, pp. 47-59. Grossman, G. Krueger, A., 1991. Environmental Impacts of a North American Free Trade Agreement, Cambridge, MA: National Bureau of Economic Research. Ilkensen, D., 2009. Burning Rubber: Proposed Duties on Chinese Tyres Whiff of Senseless Protectionism. Free Trade Bulletin, Volume 39, pp. 1-4. Ilkensen, D., 2009. No Longer Us Versus Them, London: International Policy Network. Joseph, S., 2013. Blame it on the WTO. Oxford: Oxford University Press. Krasner, S. Webb, M., 1989. Hegemonic Stability Theory: an empirical assessment. Review of International Studies, 15(2), pp. 183-198. Lanoszka, A., 2009. The World Trade Organisation: changing dynamics in the global political economy. London: Lynne Rienner. Scruton, R., 2006. A Political Philosophy. London: Bloomsbury. Stern, D., Common, M. Barbier, E., 1996. Economic Growth and Environmental Dgeradation: The Environmental Kuznets Curve and Sustainable Development. World Development, 24(7), pp. 1151-1160. Stiglitz, J. Charlton, A., 2007. Fair Trade For All. Oxford: Oxford University Press. Subramanian, A., 2007. The WTO Promotes Trade, Strongly but Unevenly. Journal of International Economics, Volume 72, pp. 151-175.