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. 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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