Finance Essay Example | Topics and Well Written Essays - 3000 words - 2

Finance - Essay Example Here the opportunity cost of capital is assumed to be 12%. Thus by adopting it as the discount rate for all future cash flows one can effectively obtain the NPV for them. This gives a few advantages. In the first place proper financial management requires a realistic opportunity cost to be set against capital. Though over a period of 5 years there can be considerable pressure on interest rates, a steady return of earnings would be ensured through proper cash flow management. After all the above cash flow forecasts are assumed to be constant though, in reality they might vary. The decision to make the investment is based on the apparent returns by way of future cash flows and it does not take into account the risk factor involved. For instance the investor has totally disregarded DCF method because he probably considers those future returns to be final and conclusive with respect to their values. The DCF calculations and the NPV figure of the total investment show that the decision is fairly justifiable because the NPV is equal to  £ 123,928.60 which is a considerable value against probable future inflationary pressure, i.e. the opportunity cost of capital. The importance of discounting future cash flows by using these formulas also depends on other factors as well. Discounted cash flows give a real picture of the future possibilities. Since DCF is what an individual is willing to pay at present in order to have what he expects to have in the future, it’s a process of expressing future revenue flows in terms of today’s value. Probably the most important reason behind DCF is the fact that inflation erodes the value of money in times to come, i.e. future. Therefore it’s essential to make up for the loss. That is why in each subsequent DCF multiplied by the number of years, a lower value comes up. The Internal Rate of Return (IRR) sets the present value of all future cash flows of an investment equal to zero.

Ken Frazier Case Study Essay Example | Topics and Well Written Essays - 500 words

Ken Frazier Case Study - Essay Example In this effect, Ken single gave the company its modern status by redeeming it from a possible pit that it would not rescue itself. A learning organization depends on initiative and innovation as its greatest and valuable assets. In addition, it embraces employee empowerment, creativity and takes risks in a desire to achieve its objectives. Based on this explanation, the Merck Company is a learning organization based on the risk it takes in appoints Ken as its CEO (Lussier & Christopher, 2013). Furthermore, it prioritizes innovation and creativity in its scientific application and the process of drug manufacturing. Specifically, this is through investing millions of dollars in a drug process whose certainty is unclear. Enhancing innovation is imperative for its success. In that accord, there are several actions that the CEO should eliminate or put in place to facilitate this practice. First, he should avoid the creation of rules on how activities are carried out (Lussier & Christopher, 2013). Instead, he should create a possibility box that can contain all the ideas of the workers and other essential stakeholders. Additionally, he eliminates fears of failure, making mistakes, and the fear of looking foolish and assumes an active personality. Frazier has articulated a strategy that gives the customers a center stage by carrying out market research and analysis to determine the requirement in the market. As confirmed by a board member William B. Harrison, Ken has the strategic vision, operational experience, and passion for leading the company in achieving its goals (Lussier & Christopher, 2013). Among the supporting factors that lead to the appointment of Ken as the CEO is the talent he displayed in handling a crisis in defending the Vioxx drug. Additionally, he carried out a market research in a special way that gave the firm its competitive edge

Organisational Structure Essay Example for Free

Organisational Structure Essay All organisations are designed to suit their objectives, role, and mission. Internal structure of an organisation is the way in which interrelated groups of an organisation are arranged in a particular fashion for effective communication and best possible coordination (Wikipedia, 2006). Organisational structure plays an important role in day-to-day functions of an organization. The organisational structure of an organization will dictate the delegation of authority, work specialization, and employee reporting framework. An efficient structure will facilitate decision making. A good organisational structure removes uncertainties and helps in planning for future expansion as well (Business Bureau-uk, 2002). A company would adopt a suitable combination of structure and control systems that are most effective for pursuing sustainable competitive advantage. In addition to coordinating strategy implementation, the role of structure and control is to motivate and provide incentives for superior performance. There are numerous internal and external factors affecting the way organizations structure themselves. This essay will scrutinize organisational structures of small and medium sized organizations in different countries. An evaluation of the factors affecting these structures has also been carried out coupled with an analysis of the response from these organizations to varying challenges. Organisational Structures Three major components of organisational structure identified by most theorists include complexity, formalisation, and centralisation (Robbins, 1987). Complexity is basically the degree of differentiation that exists within an organization. Horizontal differentiation considers the degree of separation between units of the same level and vertical differentiation refers to the depth of the organizational hierarchy. A well-known way of horizontal differentiation is the multidivisional (M-form) structure (Chandler, 1962). This structural form is used by firms to carry out most diverse economic activities. Other forms of horizontal differentiation are the functional structure in which people and tasks are grouped together on the basis of their common expertise and experience. Then there are the geographic structures, which use regional basis for organizing activities, and the product division structure which has a focus on products or product groups. The second component of organisational structure is the formalisation. The formalisation refers to the degree to which jobs within the organization are standardized. If a job is highly formalized, there are explicit job descriptions, lots of organizational rules, and clearly defined procedures. The formal organization however does not imply that the organisational structure will become inflexible. The informal organization on the other hand is any joint activity without conscious joint purpose, even though contributing to joint results (Barnard, 1964). The third component of organisational structure is the centralisation. It is defined by most theorists as the degree to which decision making is concentrated at a single point in the organization. Small and Medium-sized Enterprises (SMEs) in Different Countries SMEs are generally defined as having fewer than 250 employees and less than 50 million euros in annual turnover (Cardais, 2005). SMEs play a major role in developed economies. According to the United Nations Economic Commission for Europe, in 2000, 99. 8 per cent of enterprises in 19 countries in Western Europe were SMEs (Kuwayama, 2002). In the United States, small businesses employ more than half of the labor force. The SMEs constitute 96% of the total establishments and represented 69% of total employment in the US (APEC, 2006). SMEs are inherently adaptive to changing market and supply environments. SMEs help in deepening managerial and entrepreneurial skills, and are considered very attractive because of their diversity and competition in the supply of products and services. In United States, SMEs generate half of the national total sales. Most of these corporations develop market-like relationships between the different parts of their organisation. This is reflected in the greater use of the multidivisional structure form. In United States, companies are split into profit centres in pursuance of their market strategies. There is however heavy reliance on formal procedures and standardisation of organisational roles which makes American companies to coordinate a large diversity of economic activities. In Europe, 20 million small and medium sized enterprises comprise major chunk of the European economy. The SMEs in Eurpoe are providing around 65 million jobs. SMEs have greater opportunities to continuously evlove their structures keeping in view their diversified role and constantly changing competitive environments. Organisational Structure of SMEs is very dynamic in Europe. In Germany specially, SMEs are more centralized than US companies and planning and control is more integrated (Europa, 2006). The German SMEs are characterised by a strong linkage between enterprise and owner. This close relationship strongly influences the internal structure and market strategies of the enterprises (Hauser, 2000, pp. 1-2). Factors Reshaping Organisations There are many internal and external forces that can affect an organization. Internally an organization creates its own internal structure, mission, and fiscal policies. These internal forces are designed to meet the external challenges like competitors, the economy, and the demands of the customers. All these factors are having unified impact on organizations in United States and in Europe. Customer demands are influencing organizational structures directly in the same manner that supply can affect demand and vice versa. Another area influencing organizational designs is the constantly changing requirements of the human resources. Surveys conducted in United States have revealed changing workforce behaviour. Changing drives for motivating workers, and getting the best out of them affects the way a company needs to organise its resources. SMEs in developed economies are influenced by e-business to a great extent, allowing them to trade worldwide from a single website. Organisations in Europe and United States are deeply effected by the environment. The advancement of technology is forcing the companies to reengineer their processes. The general environment is dictating change in socio-cultural outlook of companies. With regard to the task environment, major forces playing their part in reshaping organisations include competitors, customers, suppliers, regulators, and strategic allies. High performance and customer satisfaction are directly related to structural design of a company. To compete effectively, the company must avoid becoming operated by a top-down approach. In an era of rapid change and high technology, companies are required to shift centralized management controls. The environment is dictating to focus on streamlining operations, and empowering workers with the knowledge, skills and resources to do their jobs. Analysis of Response to Changing Requirements Change is always viewed differently by the management and the employees. Top level management perceives change as an opportunity to strengthen the business and to advance in their career. The employees however do not welcome the change. They consider change as disruptive and intrusive. They may worry about their ability to meet new job demands. They may think that their job security is threatened, or they may simply dislike ambiguity. Some managers may also feel threatened by the change since it may be against their self-interests. Managers so affected may fight the change as well. But the change is inevitable. The only thing constant in this world is the change. Organizations in Europe and United States are changing and actively adapting to their environments. Organisations in United States are structuring to small business units to tackle complex, and highly uncertain environments in the face of huge competition. Organizations whose structures are not fitted to the environment can not perform well and eventually fail (Borgatti, 1996). The changes are being made to the tools, resources, and the physical or organizational settings of the company. Organisations in Europe and United States are redesigning their structures to meet new challenges. Customers, owners, suppliers, regulators, local communities, and other employees are changing their needs constantly which are compelling the SMEs to adopt a flexible and dynamic structure. The Impact of uncertainty avoidance dimension is forcing towards flexibility of jobs definition and task interchangeability which is quite visible in US and European companies nowadays (Hofstede, 1980). Conclusion The last decade of 20th century witnessed developments occurring within a frame work of rapidly expanding social and economic interdependence on a global scale. Organizations have evolved through periods of incremental or evolutionary change. The major work changes happening today are changes in organizational strategy, organizational structure and design, technology and human resources. In contrast to the classical scholars, most theorists today believe that there is no one best way to organize. What is important is that there be a fit between the organizations structure, its size, its technology, and the requirements of the environment including the competitors. References http://www.actetsme.org/usa/usa98.htm http://www.analytictech.com/mb021/orgtheory.htm http://en.wikipedia.org/wiki/Organizational_structure

Aetiology of Gestational Diabetes Mellitus

Aetiology of Gestational Diabetes Mellitus Abstract Gestational Diabetes is a condition present in the later stages of pregnancy where the mother has insulin resistance leading to glucose intolerance. The aetiology of Gestational Diabetes Mellitus is largely unknown but several theories include autoimmune destruction of the beta cells, monogenic mutations and insulin resistance. In pregnancy it is normal for there to be some levels of insulin resistance and it is thought that the products of the placenta contribute to the state of insulin resistance as GDM usually subsides after pregnancy. GDM in pregnancy can lead to an increased risk of cardiovascular disease in the offspring such as hypertension and atherosclerosis. This is due to the increased levels of oxidative stress and inflammatory mediators present during pregnancy. The placenta is very important as it is able to control and buffer the amount of glucose that is delivered to the fetus but if this level is too high then it is out of the placentas control and the fetus may have increased rate of growth due to this extra glucose. The current focus of research in this area seems to be into finding ways to diagnosis GDM earlier in the pregnancy and to try and reduce the amounts of oxidative stress. Gestational diabetes: consequences for fetal programming of vascular disease in adulthood Introduction Gestational Diabetes Mellitus (GDM) occurs when there is a glucose intolerance that is first detected during pregnancy. It is a form of hyperglycaemia (Buchanan and Xiang 2005). The aetiology of the condition is unknown but there have been many suggestions as to the cause of it, including autoimmune destruction of the ß pancreatic cells and the possibility of a genetic predisposition to the condition. Hormones that are produced in pregnancy help contribute to the insulin resistant state which characterises diabetes. In recent years, there has been an increase in the cases of Obesity and this is a risk factor for both Diabetes Mellitus and Cardiovascular Disease. The intrauterine environment can affect fetal programming and development. This essay will look into how the placenta and its products can affect the insulin resistant state and how this resistance effects programming as well as the role of oxidative stress and inflammation in making the offspring more susceptible to cardi ovascular disease. Gestational Diabetes Mellitus (GDM) GDM is a state of insulin resistance which disturbs the intrauterine environment and can lead to accelerated fetal growth (Radaelli et al 2003).It effects approximately 7% of pregnant women with approximately 200,000 cases seen each year (Schillan-Koliopoulos and Guadagno 2006). The term GDM is applicable when the onset is during the second and third terms of the pregnancy, but it does not exclude the possibility that the insulin resistance was undiagnosed before the pregnancy. If this is the case and is found to occur in the earlier stages of pregnancy then the mother should be treated the same as mothers who are known to have diabetes before pregnancy (Metzger, Coustan 1998). There is a degree of insulin resistance in normal pregnancy which begins towards the middle of the pregnancy but during the later part of the second and the final trimester these can increase to levels of insulin resistance that are associated with type 2 diabetes (Yogev et al 2008 Chapter 10). Insulin resista nce is when the tissues do not produce a response to insulin due to problems with the secretion of insulin or where the tissues are desensitised to insulin and therefore lack the ability to produce a response (Catalano et al 2003). In a normal pregnancy, the mother changes her metabolism to allow a constant supply of nutrients to reach the fetus to support its rapid growth. Among these nutrients is glucose, which is the main energy source used by the fetus. During the later stages of pregnancy the mother becomes hypoglycaemic and although there is increased gluconeogenesis, the hypoglycaemia still occurs because there is a high rate of transport of glucose to the fetus (Herrera 2000 cited in Herrera and Ortega 2008). GDM can have effects that impact the development of the fetus such as hypoglycaemia and macrosomia, which is an increase in body weight and has the possibility of leading to problems when giving birth, such as shoulder dystocia (Schillan-Koliopoulos and Guadagno 2006). During the second trimester of pregnancy there is peripheral insulin resistance but there is also the possibility that hepatic insulin sensitivity is altered in pregnancy, although few studies confirm this. By the end of the pregnancy the levels of insulin that are circulating are thought to be double those at the start (Redman 2001). Insulin Resistance Insulin resistance in GDM can occur in two forms. The first is where it develops in late pregnancy and it has been postulated that there is a post-receptor mechanism that may influence the insulin signalling pathway which leads to a reduced glucose uptake. The second form is where there is already a degree of resistance before the pregnancy but the changes that occur in normal pregnancy aggravate this (Metznger et al 2007). The insulin resistance that develops in pregnancy is much needed to allow the flow of nutrients, from the mother, directly to the fetus to allow for growth (Radaelli 2003). Increased insulin resistance leads to an increase in insulin secretion by the ß pancreatic cells (Buchanan and Xiang 2005). The insulin resistance is thought to be caused by increased adiposity and as the insulin resistance usually stops after pregnancy this suggests that there is a possibility that the products of the placenta are a potential cause of the resistance. During the course of th e pregnancy the actual changes in glucose levels are very small. It would be assumed that the glucose levels would rise due to the increased insulin resistance but the pancreatic ß cells increase their secretion of insulin to maintain homeostatic glucose levels (Yogev et al 2008 Chapter 10). GDM occurs because there is an increased demand for insulin which under normal circumstances can be met unless there are problems with the secretion of insulin leading to the development of hyperglycaemia. The majority of mothers who develop GDM have been discovered to have a degree of insulin resistance before they became pregnant. Therefore, with the insulin resistance that occurs in normal pregnancy it can be said that GDM occurs with a greater insulin resistance than normally present in gestation (Yogev et al 2008 Chapter 10). Insulin resistance causes a decreased uptake of glucose into skeletal muscle, adipose tissue and liver as well as a decreased production of hepatic glucose. (Catala no et al 2003). One suggestion for insulin resistance looks into the possible role of the mitochondria. Studies using Magnetic Resonance Spectroscopy (MRS) have shown that in normal offspring of parents with type 2 diabetes, there is an increased amount of intramyocellular lipid. This has been shown to cause a reduced function in mitochondria which suggests that mitochondrial dysfunction may play a part in insulin resistance (Petersen et al 2004 cited in Morino et al 2005). It has been suggested that this increase in intramyocellular lipid activates a serine kinase cascade which causes an increase in the Insulin Substrate Receptor 1 (IRS-1), which inhibits insulin receptor phosphorylation on tyrosine sites. This can cause a decrease in the effects and utilisation of glucose. One study showed that in the insulin resistant offspring the mitochondrial density was reduced by just over a third to that of a normal offspring. This suggests that offspring who are insulin resistant may inher it a condition that causes a reduction in rate oxidative phosphorylation in mitochondria (Griffin et al 2009 cited in Morino et al 2005). Detection of GDM Diagnosis of GDM helps to identify pregnancies that are at risk of fetal morbidity as well as obesity and glucose intolerance in the offspring (Buchanan and Xiang 2005). GDM is hard to diagnose as it is asymptomatic. Normal diabetes could be diagnosed by glycosuria but in pregnancy the renal threshold to glucose is lowered so that glycosuria doesnt give a true representation of hyperglycaemia (Redman 2001). There are several risk factors of GDM which can be classified into three groups and help in the screening process. Low risk factors include women who are younger than 25, normal weight at conception, no known family members with diabetes and no history of glucose intolerance. High risk factors include obesity of the mother, diabetes in close relatives, a history of glucose intolerance, current glycosuria and previous pregnancies with GDM (Metzger and Coustan 1998 Chapter 25). Causes of Diabetes There are several theories as to why diabetes occurs and this has been thought to be similar to the underlying mechanisms that cause gestational diabetes. Diabetes is a result of pancreatic beta-cell dysfunction which can present in three main ways: autoimmune, a genetic cause and on top of already present insulin resistance (Buchanan and Xiang 2005). Autoimmune diabetes accounts for approximately 5-10% of all diabetic cases (American Diabetes Association 2010). There are circulating antibodies to the ß cells of the Islet of Langerhans. In GDM, there are a small number of women who have with these antibodies present in their circulation. It is thought that these cases present with GDM due to problems with insulin secretion caused by destruction of the Islets by the autoantibodies (Buchanan and Xiang 2005). This form is similar to type 1 diabetes. The Islet Cell Autoantibodies (ICA) have been shown to have four major molecular targets: Insulin, Glutamic acid decarboxylase (GAD 65), Insulinoma-associated antigen-2 (IA-2) and Zinc Transporter 8 (ZnT8) (Tree 2010). Monogenic diabetes has 2 general forms, one where there are mutations in autosomes and the other where there are mutations in the DNA of mitochondria. The first form is commonly referred to as Maturity Onset Diabetes of the Young (MODY). In both cases onset tends to be at a young age and the patient doesnt present with insulin resistance or obesity (Buchanan and Xiang 2005). Mutations that cause MODY have been found in some women with GDM and commonly occur in genes coding for glucokinase, hepatocyte nuclear factor and insulin promoter factor, MODY is associated with beta cell dysfunction (Weng et al 2002). Chronic insulin resistance with beta-cell dysfunction seems to be the most common cause of GDM. As mentioned before there is an increase in insulin resistance in normal pregnancy but if this develops with background insulin resistance then there is an even greater insulin resistance which can lead to GDM. An established suggestion is that women who are unable to increase their secretion of insulin to cope with the insulin resistance developed in late pregnancy are more susceptible to developing GDM (Buchanan and Xiang 2005). However there could be various environmental processes that are involved in the underlying pathophysiology of GDM. The products of the placenta may also have a role in increasing or decreasing insulin resistance and these will be discussed later. Placental Function The placenta is an organ that has many roles during the development of the fetus. One of these functions is that it acts as a barrier to separate the maternal and fetal surfaces such that the syncytiotrophoblast surface exposes the placenta to the maternal circulation and the endothelium is exposed to the fetal circulation. This position between the two circulations means that the placenta is influenced by molecules from both circulatory systems, including cytokines, hormones and growth factors. The placenta produces molecules which can separately affect the maternal and fetal circulation and it expresses a large number of cytokines including leptin, resistin and tumour necrosis factor. However it has been discovered that these molecules are also produced by adipocytes. All molecules that are going from the mother to the fetus have to cross the placenta. Here they are either modified, for example lipids or like glucose, they are metabolised for placental purposes (Desoye et al 2008). The placenta plays an important role in fetal growth and the regulation of pregnancy (Giachini 2008). The placenta acts to sustain normal homeostatic levels and to carry out the functions of the vital organs. It also provides an immunological defence to the fetus and allows the exchange of molecules vital to its development (Jansson and Taylor 2007). Placental Development Approximately 4-5 days after conception, the process of cleavage causes rapid cell divisions and one of the groups of cells to form are called trophoblast cells. Further developmental processes form the blastocyte which is surrounded by an outer layer of the trophoblast cells. As the pregnancy progresses, the trophoblast cells develop into the placenta while the inner parts of the blastocyte form the embryo and umbilical cord (Huppertz 2008). The blastocyte implants itself onto the epithelium of the uterus where it differentiates into a syncitiotrophoblast which is able to implant itself in the epithelium leading to it being embedded into the decidual part of the uterus (Huppertz 2008). After the attachment of the blastocyte, the trophoblast layer divides very quickly and changes into 2 layers; the inner cytotrophoblastic layer and the outer syncytiotrophoblastic mass (Gude et al 2004).The whole implantation process takes 12 days to complete and after this the fetus is fully embedded into the endometrial layer (Huppertz 2008). The chorionic plate is the surface of the placenta that faces the fetus and this is where the umbilical cord inserts. The basal plate is the surface that faces the mother which contains many types of cells including immune cells such as macrophages and killer cells to carry out the placentas immunological function. The maternal basal plate and the fetal chorionic plate converge to form the smooth chorion which is composed of three layers (Huppertz 2008). When the trophopblast invades the endothelium there is a remodelling of the uterine spinal arteries which is necessary to ensure that the fetus and the placenta receive an adequate blood and nutrient supply and is able to remove any waste materials. This direct supply of blood and nutrients to the placenta can define it as being haemochorial villous organ (Gude et al 2004). After the rapid divisions of the trophoblast and development into 2 layers there are two pathways that can occur, th e villous and extravillious pathways. The extravillious pathway results in the trophoblast being able to invade into the decidua and cause the remodelling of the uterine arteries to increase blood supply to the placento-fetal unit. The villious pathway has a transportation function as well as having endocrine and protective functions (Gude et al 2004). Normal Placentation Placentation involves the structure and function of the placenta. The process of placentation is helped by the composition and arrangement of the extracellular matrix (ECM) of the endometrium. Studies on rats induced with diabetes provided results that showed that diabetes has an effect on the distribution of the ECM molecules. This study by Giachini et al illustrates that Types I and III collagen as well as other molecules, such as proteoglycan molecules decorin and biglycan were distributed throughout normal and diabetic placentas. It was shown that diabetes affects the expression of fibronectin and an increase in deposition of fibronectin may cause changes to the ECM structure which could affect the transfer of molecules from the mother to the fetus. One way in which changes in the ECM can be overcome is to test blood glucose levels frequently during the pregnancy and if kept in normal ranges this can dramatically decrease the prevalence of diseases and disorders present in the fe tus (Giachini et al 2008). As the pregnancy progresses the size of the placenta increases which also means an increase in the amount of products that the placenta produces therefore increasing in the insulin resistance (Schillan-Koliopoulos and Guadagno 2006). This is because the net effect of the products of the placenta is to increase insulin resistance. The increase in size of the placenta means that it needs an increased blood supply. Failure of the mother to increase its blood supply to the placenta can lead to placental insuffiency which if exacerbated can be attributed to be a cause of intrauterine growth restriction (IUGR). This growth restriction is more related to poor maternal nutrition rather than to a cause of GDM. GDM have been associated with an increased fetal and placental weight (Jansson and Taylor 2007). One of the reasons why GDM and increased insulin resistance affects the fetus is that while glucose can cross the placenta, insulin is unable to. This means that the fetal pancreas has to compensate by producing more insulin to prevent high blood glucose levels. The fetal pancreas is capable of doing this and the liver responds to the higher levels of insulin by increasing its production of glucose (Schillan-Koliopoulos and Guadagno 2006). Offspring who have an increase in birth weight have been shown to be at risk of developing cardiovascular disease and diabetes later in life. The main risk factor for this is poor transfer of nutrients via the placenta (Jansson and Taylor 2007). How dramatic these changes are depends on how good the control of blood glucose levels have been during the development of the placenta, if any treatment has been received and if there were any periods of away from normal glucose levels (Desoye 2006). How does diabetes affect Placentation? Diabetic insults at the beginning of the pregnancy can have long last effects of the placenta. One of the roles of the placenta is that it is able to buffer excess maternal glucose which can help to keep the fetal glucose levels within range However if the insult lasts longer than the placenta is able to compensate for then excessive fetal growth may occur (Desoye Mouzon 2007). In diabetes there is endothelial dysfunction which can lead to vascular disease. The endothelial cells help to control the vascular tone of the smooth muscle lining the vasculature. They do this by producing substances that help to vasodilate the smooth muscle including Nitric Oxide, Prostacyclin and Endothelium-Derived Hyperpolarising Factor (EDHF). There have been several studies to suggest different mechanisms of how diabetes affects the endothelium including impaired release of these vasodilating molecules, faults with signal transduction and increased release of constricting mediators of the endothelium. The dysfunction of the endothelium in diabetes is thought to be caused by activation of protein kinase C (PKC) as well as increased oxidative stress, non-enzymatic glycation and an increased activation of the polyol pathway (De Vries et al 2000).The main reason why these effects occur is thought to be due the activation of the protein kinase C pathway and the increased oxidative stress. This can cause early damage to the development of vascular vessels (Roberts and Raspollini 2008). These mechanisms will be discussed later. The effect of hormones produced in pregnancy Pregnancy causes changes in the circulating hormones and cytokines which can all have different effects on insulin resistance and this may help explain the mechanism underlying the resistance that is found in pregnancy and in GDM. Cytokines produced in pregnancy, such as TNF-a, Adiponectin and Leptin have been found to cause an increase in the insulin resistance (Gao et al 2008). In early pregnancy, the levels of oestrogen and progesterone rise but no net effect is seen as the two have antagonistic effects. Oestrogen increases the binding of insulin to its receptor whereas progesterone reduces the ability of insulin to bind (Ryan and Enns 1988). Cortisol levels in pregnancy increase so that by the end of the pregnancy the levels are three times that of what they were at the beginning (Gibson and Tulchinski 1980 cited in Yogev et al Chapter 10). Studies have shown that with increased amounts of cortisol there was a decrease in insulin sensitivity causing insulin resistance (Rizza et a l 1982 cited in Yogev et al 2008 chapter 10). During pregnancy the levels of prolactin increase up to ten times the normal amount (Yogev et al 2008 chapter 10). Studies have shown that in a culture of pancreatic beta cells, prolactin can cause an increase in levels of secreted insulin (Sorenson et al 1993 cited in Yogev et al 2008 Chapter 10). However, high levels of prolactin are not seen to be a pathological cause of GDM (Yogev et al 2008 chapter 10). Human placental lactogen (HPL) is a hormone, and its levels rise during the second trimester of pregnancy. This causes a decrease in the phosphorylation of insulin receptor substrate (IRS1) which can lead to significant insulin resistance (Ryan and Enns 2008 cited Yogev et al 2008 ch 10). Leptin is associated with obesity and concentrations of leptin have been shown to be related to the concentration of insulin in the plasma. In pregnancy the leptin levels increase dramatically. During pregnancy the mother uses her fat stores to supp ort fetal growth and it is thought that the leptin levels increase with the mobilisation of these fat stores. Leptin levels relate to the body mass of the individual (Sattar et al 1998). Placental Leptin is the same in structure and charge to the one produced by adipose tissue (Ashworth et al 2000). One study showed that high leptin concentrations in the umbilical cord increased the likelihood of developing fetal macrosomia (Wiznitzer et al 2000). It is also thought that leptin effects insulin sensitivity by effecting glucose metabolism in both skeletal muscle and in hepatocytes. Rats that received an external source of leptin were found to have an increase in gluconeogenesis which accounted for the majority of hepatic glucose production (Rossetti et al 1997). In GDM there is a greater secretion of TNF-alpha in response to glucose. TNF-alpha functions to regulate metabolism of glucose and lipids as well as being involved in insulin resistance. Many studies suggest that TNF-alpha is involved in the progression to GDM. They found that an increase in glucose cause the placenta and adipose tissue to increase production of TNF-alpha in some cases up to 4 times more than non-diabetic pregnant(Coughlan et al 2001). One study showed that the increases in the levels of TNF-alpha during pregnancy increased consistently with increases in body weight (Catalano et al cited in Yogev et al 2008). Adiponectin is a protein derived from adipose tissue and its function is to regulate insulin resistance and maintains levels of glucose. During pregnancy it has been found that its levels drop and could therefore lead to the increase insulin resistance found in GDM (Gao, Yang, Zao 2008). Adiponectin has also been found to decrease the secretion of TNF-alpha which as stated above can lead to insulin resistance (Hotamisligil 1999 cited in Yogev et al Chapter 10 2008). Adiponectin may cause increased insulin sensitivity as its concentration decreases throughout the gestational period ( Desoye and Mouzon 2007). Resistin is a protein that is produced by adipose tissue and is thought to be involved in insulin resistance in diabetes and is associated with obesity (Steppan and Lazar 2002) In pregnancy, resistin is secreted by the placenta and this secretion reaches its peak by the last trimester (Yura et al cited in Megia et al 2008). Studies show that TNF-alpha is an important factor in insulin resistance during pregnancy and with inputs from leptin and cortisol there is altered glucose metabolism whereas inputs from oestrogen, progesterone and prolactin had little significant effects (Kirwan and Mouzon 2002). There are many hormones produced during pregnancy, mainly by the placenta and adipose tissue that have varying affects but with the overall impact being insulin resistance. Inflammation in Diabetes There are genes in the placenta which regulate reorganisation of the endothelium and inflammatory responses and in GDM these were found to be altered. The increase in leptin receptors suggests that in the placenta this can cause proinflammatory responses (Radaelli 2003). One of the current theories is that the abnormal metabolic environment in GDM can lead to increased production of cytokines and inflammatory mediators. Molecules such as TNF-alpha, Resistin and Leptin increase during pregnancy and these increases in these inflammatory mediators produce metabolic changes by increasing insulin resistance (Desoye and Mouzon 2007). Leptin and TNF-alpha activate phospholipase A2 which are a family of eicosanoid precursors that go on to produce essential fatty acids such as w3 polyunsaturated fatty acids (Desoye Mouzon 2007). There has been a recent investigation which found that with increased adiposity at birth there has been an increase in w3 fatty acids in the placenta (Verastehpour et al 2005 cited Desoye and Mouzon 2007). As stated before, the placenta produces cytokines but it is also a site of action of the cytokines. It is the location of the receptors for these cytokines will influence if the cytokines act on the mother, the placenta or the fetus. With cytokines there is very little transfer across the placenta from mother to fetus and the origin of the cytokines in the fetus can be from either the placenta or from the fetus itself (Desoye and Mouzon 2007). Fetal Programming Many studies have highlighted the fact that events that occur while the fetus is developing can alter its developmental pathway and have adverse outcomes in later life. Fetal programming describes how the environment can affect certain developmental events of which the effects are permanent and can affect processes such as metabolism and the organisms physiology. Women with GDM have an increased risk of the fetus developing macrosomia (Catalano 2008 Chapter 11). The main factor that effects the growth of the fetus is the maternal environment and there is a strong association with the weight and height of the mother and the growth of the fetus such that mothers who are heavier and taller will produce heavy babies. (Love and Kinch 1965 cited in Catalano 2008 Chapter 11). The placenta and fetal programming The placenta is very important to the developmental processes of the fetus as it is able to change the quantity of signals and nutrients that the fetus receives. Deviation from normal would alter the fetal programming, thus making it more susceptible to disease in later life. Pregnancies that are complicated by GDM have excessive oxidative and nitrate stress which has been found to change the activity of certain proteins. Oxidative and nitrate stress alter the placentas function and may cause changes in the fetal programming. Nutrient transfer depends largely on the normal development of the vasculature to allow blood flow and this can be affected by GDM which can cause a decrease in the flow of substrates and is a mechanism in which fetal programming can be affected (Myatt 2006). Fetal programming involves a large amount of development plasticity and interruptions to this development may cause abnormalities in the development of certain cells which may progress to structural differe nces in organ development (Gluckman and Hanson 2004 cited in Jansson and Powell 2008 ref 16). Effects to the fetus exposed to GDM If a fetus is exposed to a diabetic environment during pregnancy then there can be certain long term effects. These effects can be classified into three groups; Anthropometric, Metabolic or Vascular and Neurological or Psychological. Anthropometric changes are concerned with the rates of growth for both height and weight and in a diabetic environment these can be excessive leading to macrosomia and obesity in later life. Metabolic and vascular changes that occur are abnormal glucose tolerance which can eventually lead to diabetes mellitus. Finally the neurological and psychological changes that can occur are usually minor but development of psychological and intellect can sometimes be deficient (Dabelea and Pettitt 2008). Potential problems that may arise with the fetus from an exposure to maternal diabetes include abnormal organ mass, altered angiogenesis and increased levels of fetal insulin (Fetita 2006). It has also been found that if there is an increase in weight during pregnan cy then there is usually a higher birth weight of the fetus (Humphreys 1954 cited in Catalano 2008 Chapter 11). The developing fetus cannot synthesise glucose and is dependent on the mother to produce it where it is transported to the fetus via facilitated diffusion through the placenta (Aerts et al 1996 cited in Mello, Parretti and Hod 2008). The result of decreased insulin sensitivity is that there is more glucose available to the developing fetus which can lead to a greater birth weight (Mello, Parretti and Hod 2008). Using animal models, it has been shown that exposure to high levels of glucose in utero can lead a diminished number of nephrons in the offspring (Amri et al 1999 cited in Fetita 2006 ref 68). This is important as nephrogenesis only occurs in the fetus and stops after birth (Gomez, Norwood 1999). It has been shown that a reduction in the numbers of nephron may affect the rate of progression of renal disease in adults due to an inability to secrete sodium. This may l ater develop into salt-sensitive hypertension (Brenner et al 1988). The mechanisms of reduced organ mass, high levels of fetal insulin and defects in angiogenesis may help explain how the fetus programs abnormal glucose tolerance in adulthood as a result of exposure to GDM (Fetita 2006). Transmission of diabetes from mother to offspring Exposure to gestational diabetes mellitus increases the risk of the fetus developing abnormal glucose tolerance which may develop into type 2 diabetes. (Fetita et al 2006). The association between greater incidences of the offspring having diabetes with a mother with GDM is greater than what would be predicted that could be passed on by maternal genetics (McLean et al 2006). One study showed that the phenotype for GDM/T2D was more common in daughters of mothers who were diabetic rather than daughters of fathers who were diabetic suggesting that the transmission is from mothers with GDM to their daughters. However there were limitations of the McLean study. Patients may not be aware of their fathers diabetes status due to men having lower inclinations to report symptoms and share illnesses with the family. One study showed that the mass of the pancreatic beta cells is relatively fixed by the end of fetal growth and this can be influenced by an intrauterine environment of hyperglycaema (McLean et al 2006). Congenital defects are more common in babies born to diabetic mothers (Farrel et al 2002 cited in Fetita et al 2006). There are many factors that can influence the prevalence of these malformations including the duration, severity and age of onset of GDM (Kousseff 1999). If the onset of GDM is at the beginning of development then development of some organs may be affected. However as said before, the majority of GDM develops during the second trimester. This can then lead to embryopathy which includes defects such as failure of neural tube closure and malformations in the Renal, Cardiac and Gastrointestinal systems which present in childhood (Fetita 2006). In diabetes the hexosamine pathway is activated and inhibits the pentose shunt pathway which decreases the production of antioxidants and therefore leads to an increase in oxidative stress. This oxidative stress has been found to disrupt gene expression and may contribute to congenital defects. One example is that oxidative stress inhibits a gene called pax-3 which is needed for neural tube closure and in diabetes there is an increased risk of neural tube defects (Horal et al 20 Aetiology of Gestational Diabetes Mellitus Aetiology of Gestational Diabetes Mellitus Abstract Gestational Diabetes is a condition present in the later stages of pregnancy where the mother has insulin resistance leading to glucose intolerance. The aetiology of Gestational Diabetes Mellitus is largely unknown but several theories include autoimmune destruction of the beta cells, monogenic mutations and insulin resistance. In pregnancy it is normal for there to be some levels of insulin resistance and it is thought that the products of the placenta contribute to the state of insulin resistance as GDM usually subsides after pregnancy. GDM in pregnancy can lead to an increased risk of cardiovascular disease in the offspring such as hypertension and atherosclerosis. This is due to the increased levels of oxidative stress and inflammatory mediators present during pregnancy. The placenta is very important as it is able to control and buffer the amount of glucose that is delivered to the fetus but if this level is too high then it is out of the placentas control and the fetus may have increased rate of growth due to this extra glucose. The current focus of research in this area seems to be into finding ways to diagnosis GDM earlier in the pregnancy and to try and reduce the amounts of oxidative stress. Gestational diabetes: consequences for fetal programming of vascular disease in adulthood Introduction Gestational Diabetes Mellitus (GDM) occurs when there is a glucose intolerance that is first detected during pregnancy. It is a form of hyperglycaemia (Buchanan and Xiang 2005). The aetiology of the condition is unknown but there have been many suggestions as to the cause of it, including autoimmune destruction of the ß pancreatic cells and the possibility of a genetic predisposition to the condition. Hormones that are produced in pregnancy help contribute to the insulin resistant state which characterises diabetes. In recent years, there has been an increase in the cases of Obesity and this is a risk factor for both Diabetes Mellitus and Cardiovascular Disease. The intrauterine environment can affect fetal programming and development. This essay will look into how the placenta and its products can affect the insulin resistant state and how this resistance effects programming as well as the role of oxidative stress and inflammation in making the offspring more susceptible to cardi ovascular disease. Gestational Diabetes Mellitus (GDM) GDM is a state of insulin resistance which disturbs the intrauterine environment and can lead to accelerated fetal growth (Radaelli et al 2003).It effects approximately 7% of pregnant women with approximately 200,000 cases seen each year (Schillan-Koliopoulos and Guadagno 2006). The term GDM is applicable when the onset is during the second and third terms of the pregnancy, but it does not exclude the possibility that the insulin resistance was undiagnosed before the pregnancy. If this is the case and is found to occur in the earlier stages of pregnancy then the mother should be treated the same as mothers who are known to have diabetes before pregnancy (Metzger, Coustan 1998). There is a degree of insulin resistance in normal pregnancy which begins towards the middle of the pregnancy but during the later part of the second and the final trimester these can increase to levels of insulin resistance that are associated with type 2 diabetes (Yogev et al 2008 Chapter 10). Insulin resista nce is when the tissues do not produce a response to insulin due to problems with the secretion of insulin or where the tissues are desensitised to insulin and therefore lack the ability to produce a response (Catalano et al 2003). In a normal pregnancy, the mother changes her metabolism to allow a constant supply of nutrients to reach the fetus to support its rapid growth. Among these nutrients is glucose, which is the main energy source used by the fetus. During the later stages of pregnancy the mother becomes hypoglycaemic and although there is increased gluconeogenesis, the hypoglycaemia still occurs because there is a high rate of transport of glucose to the fetus (Herrera 2000 cited in Herrera and Ortega 2008). GDM can have effects that impact the development of the fetus such as hypoglycaemia and macrosomia, which is an increase in body weight and has the possibility of leading to problems when giving birth, such as shoulder dystocia (Schillan-Koliopoulos and Guadagno 2006). During the second trimester of pregnancy there is peripheral insulin resistance but there is also the possibility that hepatic insulin sensitivity is altered in pregnancy, although few studies confirm this. By the end of the pregnancy the levels of insulin that are circulating are thought to be double those at the start (Redman 2001). Insulin Resistance Insulin resistance in GDM can occur in two forms. The first is where it develops in late pregnancy and it has been postulated that there is a post-receptor mechanism that may influence the insulin signalling pathway which leads to a reduced glucose uptake. The second form is where there is already a degree of resistance before the pregnancy but the changes that occur in normal pregnancy aggravate this (Metznger et al 2007). The insulin resistance that develops in pregnancy is much needed to allow the flow of nutrients, from the mother, directly to the fetus to allow for growth (Radaelli 2003). Increased insulin resistance leads to an increase in insulin secretion by the ß pancreatic cells (Buchanan and Xiang 2005). The insulin resistance is thought to be caused by increased adiposity and as the insulin resistance usually stops after pregnancy this suggests that there is a possibility that the products of the placenta are a potential cause of the resistance. During the course of th e pregnancy the actual changes in glucose levels are very small. It would be assumed that the glucose levels would rise due to the increased insulin resistance but the pancreatic ß cells increase their secretion of insulin to maintain homeostatic glucose levels (Yogev et al 2008 Chapter 10). GDM occurs because there is an increased demand for insulin which under normal circumstances can be met unless there are problems with the secretion of insulin leading to the development of hyperglycaemia. The majority of mothers who develop GDM have been discovered to have a degree of insulin resistance before they became pregnant. Therefore, with the insulin resistance that occurs in normal pregnancy it can be said that GDM occurs with a greater insulin resistance than normally present in gestation (Yogev et al 2008 Chapter 10). Insulin resistance causes a decreased uptake of glucose into skeletal muscle, adipose tissue and liver as well as a decreased production of hepatic glucose. (Catala no et al 2003). One suggestion for insulin resistance looks into the possible role of the mitochondria. Studies using Magnetic Resonance Spectroscopy (MRS) have shown that in normal offspring of parents with type 2 diabetes, there is an increased amount of intramyocellular lipid. This has been shown to cause a reduced function in mitochondria which suggests that mitochondrial dysfunction may play a part in insulin resistance (Petersen et al 2004 cited in Morino et al 2005). It has been suggested that this increase in intramyocellular lipid activates a serine kinase cascade which causes an increase in the Insulin Substrate Receptor 1 (IRS-1), which inhibits insulin receptor phosphorylation on tyrosine sites. This can cause a decrease in the effects and utilisation of glucose. One study showed that in the insulin resistant offspring the mitochondrial density was reduced by just over a third to that of a normal offspring. This suggests that offspring who are insulin resistant may inher it a condition that causes a reduction in rate oxidative phosphorylation in mitochondria (Griffin et al 2009 cited in Morino et al 2005). Detection of GDM Diagnosis of GDM helps to identify pregnancies that are at risk of fetal morbidity as well as obesity and glucose intolerance in the offspring (Buchanan and Xiang 2005). GDM is hard to diagnose as it is asymptomatic. Normal diabetes could be diagnosed by glycosuria but in pregnancy the renal threshold to glucose is lowered so that glycosuria doesnt give a true representation of hyperglycaemia (Redman 2001). There are several risk factors of GDM which can be classified into three groups and help in the screening process. Low risk factors include women who are younger than 25, normal weight at conception, no known family members with diabetes and no history of glucose intolerance. High risk factors include obesity of the mother, diabetes in close relatives, a history of glucose intolerance, current glycosuria and previous pregnancies with GDM (Metzger and Coustan 1998 Chapter 25). Causes of Diabetes There are several theories as to why diabetes occurs and this has been thought to be similar to the underlying mechanisms that cause gestational diabetes. Diabetes is a result of pancreatic beta-cell dysfunction which can present in three main ways: autoimmune, a genetic cause and on top of already present insulin resistance (Buchanan and Xiang 2005). Autoimmune diabetes accounts for approximately 5-10% of all diabetic cases (American Diabetes Association 2010). There are circulating antibodies to the ß cells of the Islet of Langerhans. In GDM, there are a small number of women who have with these antibodies present in their circulation. It is thought that these cases present with GDM due to problems with insulin secretion caused by destruction of the Islets by the autoantibodies (Buchanan and Xiang 2005). This form is similar to type 1 diabetes. The Islet Cell Autoantibodies (ICA) have been shown to have four major molecular targets: Insulin, Glutamic acid decarboxylase (GAD 65), Insulinoma-associated antigen-2 (IA-2) and Zinc Transporter 8 (ZnT8) (Tree 2010). Monogenic diabetes has 2 general forms, one where there are mutations in autosomes and the other where there are mutations in the DNA of mitochondria. The first form is commonly referred to as Maturity Onset Diabetes of the Young (MODY). In both cases onset tends to be at a young age and the patient doesnt present with insulin resistance or obesity (Buchanan and Xiang 2005). Mutations that cause MODY have been found in some women with GDM and commonly occur in genes coding for glucokinase, hepatocyte nuclear factor and insulin promoter factor, MODY is associated with beta cell dysfunction (Weng et al 2002). Chronic insulin resistance with beta-cell dysfunction seems to be the most common cause of GDM. As mentioned before there is an increase in insulin resistance in normal pregnancy but if this develops with background insulin resistance then there is an even greater insulin resistance which can lead to GDM. An established suggestion is that women who are unable to increase their secretion of insulin to cope with the insulin resistance developed in late pregnancy are more susceptible to developing GDM (Buchanan and Xiang 2005). However there could be various environmental processes that are involved in the underlying pathophysiology of GDM. The products of the placenta may also have a role in increasing or decreasing insulin resistance and these will be discussed later. Placental Function The placenta is an organ that has many roles during the development of the fetus. One of these functions is that it acts as a barrier to separate the maternal and fetal surfaces such that the syncytiotrophoblast surface exposes the placenta to the maternal circulation and the endothelium is exposed to the fetal circulation. This position between the two circulations means that the placenta is influenced by molecules from both circulatory systems, including cytokines, hormones and growth factors. The placenta produces molecules which can separately affect the maternal and fetal circulation and it expresses a large number of cytokines including leptin, resistin and tumour necrosis factor. However it has been discovered that these molecules are also produced by adipocytes. All molecules that are going from the mother to the fetus have to cross the placenta. Here they are either modified, for example lipids or like glucose, they are metabolised for placental purposes (Desoye et al 2008). The placenta plays an important role in fetal growth and the regulation of pregnancy (Giachini 2008). The placenta acts to sustain normal homeostatic levels and to carry out the functions of the vital organs. It also provides an immunological defence to the fetus and allows the exchange of molecules vital to its development (Jansson and Taylor 2007). Placental Development Approximately 4-5 days after conception, the process of cleavage causes rapid cell divisions and one of the groups of cells to form are called trophoblast cells. Further developmental processes form the blastocyte which is surrounded by an outer layer of the trophoblast cells. As the pregnancy progresses, the trophoblast cells develop into the placenta while the inner parts of the blastocyte form the embryo and umbilical cord (Huppertz 2008). The blastocyte implants itself onto the epithelium of the uterus where it differentiates into a syncitiotrophoblast which is able to implant itself in the epithelium leading to it being embedded into the decidual part of the uterus (Huppertz 2008). After the attachment of the blastocyte, the trophoblast layer divides very quickly and changes into 2 layers; the inner cytotrophoblastic layer and the outer syncytiotrophoblastic mass (Gude et al 2004).The whole implantation process takes 12 days to complete and after this the fetus is fully embedded into the endometrial layer (Huppertz 2008). The chorionic plate is the surface of the placenta that faces the fetus and this is where the umbilical cord inserts. The basal plate is the surface that faces the mother which contains many types of cells including immune cells such as macrophages and killer cells to carry out the placentas immunological function. The maternal basal plate and the fetal chorionic plate converge to form the smooth chorion which is composed of three layers (Huppertz 2008). When the trophopblast invades the endothelium there is a remodelling of the uterine spinal arteries which is necessary to ensure that the fetus and the placenta receive an adequate blood and nutrient supply and is able to remove any waste materials. This direct supply of blood and nutrients to the placenta can define it as being haemochorial villous organ (Gude et al 2004). After the rapid divisions of the trophoblast and development into 2 layers there are two pathways that can occur, th e villous and extravillious pathways. The extravillious pathway results in the trophoblast being able to invade into the decidua and cause the remodelling of the uterine arteries to increase blood supply to the placento-fetal unit. The villious pathway has a transportation function as well as having endocrine and protective functions (Gude et al 2004). Normal Placentation Placentation involves the structure and function of the placenta. The process of placentation is helped by the composition and arrangement of the extracellular matrix (ECM) of the endometrium. Studies on rats induced with diabetes provided results that showed that diabetes has an effect on the distribution of the ECM molecules. This study by Giachini et al illustrates that Types I and III collagen as well as other molecules, such as proteoglycan molecules decorin and biglycan were distributed throughout normal and diabetic placentas. It was shown that diabetes affects the expression of fibronectin and an increase in deposition of fibronectin may cause changes to the ECM structure which could affect the transfer of molecules from the mother to the fetus. One way in which changes in the ECM can be overcome is to test blood glucose levels frequently during the pregnancy and if kept in normal ranges this can dramatically decrease the prevalence of diseases and disorders present in the fe tus (Giachini et al 2008). As the pregnancy progresses the size of the placenta increases which also means an increase in the amount of products that the placenta produces therefore increasing in the insulin resistance (Schillan-Koliopoulos and Guadagno 2006). This is because the net effect of the products of the placenta is to increase insulin resistance. The increase in size of the placenta means that it needs an increased blood supply. Failure of the mother to increase its blood supply to the placenta can lead to placental insuffiency which if exacerbated can be attributed to be a cause of intrauterine growth restriction (IUGR). This growth restriction is more related to poor maternal nutrition rather than to a cause of GDM. GDM have been associated with an increased fetal and placental weight (Jansson and Taylor 2007). One of the reasons why GDM and increased insulin resistance affects the fetus is that while glucose can cross the placenta, insulin is unable to. This means that the fetal pancreas has to compensate by producing more insulin to prevent high blood glucose levels. The fetal pancreas is capable of doing this and the liver responds to the higher levels of insulin by increasing its production of glucose (Schillan-Koliopoulos and Guadagno 2006). Offspring who have an increase in birth weight have been shown to be at risk of developing cardiovascular disease and diabetes later in life. The main risk factor for this is poor transfer of nutrients via the placenta (Jansson and Taylor 2007). How dramatic these changes are depends on how good the control of blood glucose levels have been during the development of the placenta, if any treatment has been received and if there were any periods of away from normal glucose levels (Desoye 2006). How does diabetes affect Placentation? Diabetic insults at the beginning of the pregnancy can have long last effects of the placenta. One of the roles of the placenta is that it is able to buffer excess maternal glucose which can help to keep the fetal glucose levels within range However if the insult lasts longer than the placenta is able to compensate for then excessive fetal growth may occur (Desoye Mouzon 2007). In diabetes there is endothelial dysfunction which can lead to vascular disease. The endothelial cells help to control the vascular tone of the smooth muscle lining the vasculature. They do this by producing substances that help to vasodilate the smooth muscle including Nitric Oxide, Prostacyclin and Endothelium-Derived Hyperpolarising Factor (EDHF). There have been several studies to suggest different mechanisms of how diabetes affects the endothelium including impaired release of these vasodilating molecules, faults with signal transduction and increased release of constricting mediators of the endothelium. The dysfunction of the endothelium in diabetes is thought to be caused by activation of protein kinase C (PKC) as well as increased oxidative stress, non-enzymatic glycation and an increased activation of the polyol pathway (De Vries et al 2000).The main reason why these effects occur is thought to be due the activation of the protein kinase C pathway and the increased oxidative stress. This can cause early damage to the development of vascular vessels (Roberts and Raspollini 2008). These mechanisms will be discussed later. The effect of hormones produced in pregnancy Pregnancy causes changes in the circulating hormones and cytokines which can all have different effects on insulin resistance and this may help explain the mechanism underlying the resistance that is found in pregnancy and in GDM. Cytokines produced in pregnancy, such as TNF-a, Adiponectin and Leptin have been found to cause an increase in the insulin resistance (Gao et al 2008). In early pregnancy, the levels of oestrogen and progesterone rise but no net effect is seen as the two have antagonistic effects. Oestrogen increases the binding of insulin to its receptor whereas progesterone reduces the ability of insulin to bind (Ryan and Enns 1988). Cortisol levels in pregnancy increase so that by the end of the pregnancy the levels are three times that of what they were at the beginning (Gibson and Tulchinski 1980 cited in Yogev et al Chapter 10). Studies have shown that with increased amounts of cortisol there was a decrease in insulin sensitivity causing insulin resistance (Rizza et a l 1982 cited in Yogev et al 2008 chapter 10). During pregnancy the levels of prolactin increase up to ten times the normal amount (Yogev et al 2008 chapter 10). Studies have shown that in a culture of pancreatic beta cells, prolactin can cause an increase in levels of secreted insulin (Sorenson et al 1993 cited in Yogev et al 2008 Chapter 10). However, high levels of prolactin are not seen to be a pathological cause of GDM (Yogev et al 2008 chapter 10). Human placental lactogen (HPL) is a hormone, and its levels rise during the second trimester of pregnancy. This causes a decrease in the phosphorylation of insulin receptor substrate (IRS1) which can lead to significant insulin resistance (Ryan and Enns 2008 cited Yogev et al 2008 ch 10). Leptin is associated with obesity and concentrations of leptin have been shown to be related to the concentration of insulin in the plasma. In pregnancy the leptin levels increase dramatically. During pregnancy the mother uses her fat stores to supp ort fetal growth and it is thought that the leptin levels increase with the mobilisation of these fat stores. Leptin levels relate to the body mass of the individual (Sattar et al 1998). Placental Leptin is the same in structure and charge to the one produced by adipose tissue (Ashworth et al 2000). One study showed that high leptin concentrations in the umbilical cord increased the likelihood of developing fetal macrosomia (Wiznitzer et al 2000). It is also thought that leptin effects insulin sensitivity by effecting glucose metabolism in both skeletal muscle and in hepatocytes. Rats that received an external source of leptin were found to have an increase in gluconeogenesis which accounted for the majority of hepatic glucose production (Rossetti et al 1997). In GDM there is a greater secretion of TNF-alpha in response to glucose. TNF-alpha functions to regulate metabolism of glucose and lipids as well as being involved in insulin resistance. Many studies suggest that TNF-alpha is involved in the progression to GDM. They found that an increase in glucose cause the placenta and adipose tissue to increase production of TNF-alpha in some cases up to 4 times more than non-diabetic pregnant(Coughlan et al 2001). One study showed that the increases in the levels of TNF-alpha during pregnancy increased consistently with increases in body weight (Catalano et al cited in Yogev et al 2008). Adiponectin is a protein derived from adipose tissue and its function is to regulate insulin resistance and maintains levels of glucose. During pregnancy it has been found that its levels drop and could therefore lead to the increase insulin resistance found in GDM (Gao, Yang, Zao 2008). Adiponectin has also been found to decrease the secretion of TNF-alpha which as stated above can lead to insulin resistance (Hotamisligil 1999 cited in Yogev et al Chapter 10 2008). Adiponectin may cause increased insulin sensitivity as its concentration decreases throughout the gestational period ( Desoye and Mouzon 2007). Resistin is a protein that is produced by adipose tissue and is thought to be involved in insulin resistance in diabetes and is associated with obesity (Steppan and Lazar 2002) In pregnancy, resistin is secreted by the placenta and this secretion reaches its peak by the last trimester (Yura et al cited in Megia et al 2008). Studies show that TNF-alpha is an important factor in insulin resistance during pregnancy and with inputs from leptin and cortisol there is altered glucose metabolism whereas inputs from oestrogen, progesterone and prolactin had little significant effects (Kirwan and Mouzon 2002). There are many hormones produced during pregnancy, mainly by the placenta and adipose tissue that have varying affects but with the overall impact being insulin resistance. Inflammation in Diabetes There are genes in the placenta which regulate reorganisation of the endothelium and inflammatory responses and in GDM these were found to be altered. The increase in leptin receptors suggests that in the placenta this can cause proinflammatory responses (Radaelli 2003). One of the current theories is that the abnormal metabolic environment in GDM can lead to increased production of cytokines and inflammatory mediators. Molecules such as TNF-alpha, Resistin and Leptin increase during pregnancy and these increases in these inflammatory mediators produce metabolic changes by increasing insulin resistance (Desoye and Mouzon 2007). Leptin and TNF-alpha activate phospholipase A2 which are a family of eicosanoid precursors that go on to produce essential fatty acids such as w3 polyunsaturated fatty acids (Desoye Mouzon 2007). There has been a recent investigation which found that with increased adiposity at birth there has been an increase in w3 fatty acids in the placenta (Verastehpour et al 2005 cited Desoye and Mouzon 2007). As stated before, the placenta produces cytokines but it is also a site of action of the cytokines. It is the location of the receptors for these cytokines will influence if the cytokines act on the mother, the placenta or the fetus. With cytokines there is very little transfer across the placenta from mother to fetus and the origin of the cytokines in the fetus can be from either the placenta or from the fetus itself (Desoye and Mouzon 2007). Fetal Programming Many studies have highlighted the fact that events that occur while the fetus is developing can alter its developmental pathway and have adverse outcomes in later life. Fetal programming describes how the environment can affect certain developmental events of which the effects are permanent and can affect processes such as metabolism and the organisms physiology. Women with GDM have an increased risk of the fetus developing macrosomia (Catalano 2008 Chapter 11). The main factor that effects the growth of the fetus is the maternal environment and there is a strong association with the weight and height of the mother and the growth of the fetus such that mothers who are heavier and taller will produce heavy babies. (Love and Kinch 1965 cited in Catalano 2008 Chapter 11). The placenta and fetal programming The placenta is very important to the developmental processes of the fetus as it is able to change the quantity of signals and nutrients that the fetus receives. Deviation from normal would alter the fetal programming, thus making it more susceptible to disease in later life. Pregnancies that are complicated by GDM have excessive oxidative and nitrate stress which has been found to change the activity of certain proteins. Oxidative and nitrate stress alter the placentas function and may cause changes in the fetal programming. Nutrient transfer depends largely on the normal development of the vasculature to allow blood flow and this can be affected by GDM which can cause a decrease in the flow of substrates and is a mechanism in which fetal programming can be affected (Myatt 2006). Fetal programming involves a large amount of development plasticity and interruptions to this development may cause abnormalities in the development of certain cells which may progress to structural differe nces in organ development (Gluckman and Hanson 2004 cited in Jansson and Powell 2008 ref 16). Effects to the fetus exposed to GDM If a fetus is exposed to a diabetic environment during pregnancy then there can be certain long term effects. These effects can be classified into three groups; Anthropometric, Metabolic or Vascular and Neurological or Psychological. Anthropometric changes are concerned with the rates of growth for both height and weight and in a diabetic environment these can be excessive leading to macrosomia and obesity in later life. Metabolic and vascular changes that occur are abnormal glucose tolerance which can eventually lead to diabetes mellitus. Finally the neurological and psychological changes that can occur are usually minor but development of psychological and intellect can sometimes be deficient (Dabelea and Pettitt 2008). Potential problems that may arise with the fetus from an exposure to maternal diabetes include abnormal organ mass, altered angiogenesis and increased levels of fetal insulin (Fetita 2006). It has also been found that if there is an increase in weight during pregnan cy then there is usually a higher birth weight of the fetus (Humphreys 1954 cited in Catalano 2008 Chapter 11). The developing fetus cannot synthesise glucose and is dependent on the mother to produce it where it is transported to the fetus via facilitated diffusion through the placenta (Aerts et al 1996 cited in Mello, Parretti and Hod 2008). The result of decreased insulin sensitivity is that there is more glucose available to the developing fetus which can lead to a greater birth weight (Mello, Parretti and Hod 2008). Using animal models, it has been shown that exposure to high levels of glucose in utero can lead a diminished number of nephrons in the offspring (Amri et al 1999 cited in Fetita 2006 ref 68). This is important as nephrogenesis only occurs in the fetus and stops after birth (Gomez, Norwood 1999). It has been shown that a reduction in the numbers of nephron may affect the rate of progression of renal disease in adults due to an inability to secrete sodium. This may l ater develop into salt-sensitive hypertension (Brenner et al 1988). The mechanisms of reduced organ mass, high levels of fetal insulin and defects in angiogenesis may help explain how the fetus programs abnormal glucose tolerance in adulthood as a result of exposure to GDM (Fetita 2006). Transmission of diabetes from mother to offspring Exposure to gestational diabetes mellitus increases the risk of the fetus developing abnormal glucose tolerance which may develop into type 2 diabetes. (Fetita et al 2006). The association between greater incidences of the offspring having diabetes with a mother with GDM is greater than what would be predicted that could be passed on by maternal genetics (McLean et al 2006). One study showed that the phenotype for GDM/T2D was more common in daughters of mothers who were diabetic rather than daughters of fathers who were diabetic suggesting that the transmission is from mothers with GDM to their daughters. However there were limitations of the McLean study. Patients may not be aware of their fathers diabetes status due to men having lower inclinations to report symptoms and share illnesses with the family. One study showed that the mass of the pancreatic beta cells is relatively fixed by the end of fetal growth and this can be influenced by an intrauterine environment of hyperglycaema (McLean et al 2006). Congenital defects are more common in babies born to diabetic mothers (Farrel et al 2002 cited in Fetita et al 2006). There are many factors that can influence the prevalence of these malformations including the duration, severity and age of onset of GDM (Kousseff 1999). If the onset of GDM is at the beginning of development then development of some organs may be affected. However as said before, the majority of GDM develops during the second trimester. This can then lead to embryopathy which includes defects such as failure of neural tube closure and malformations in the Renal, Cardiac and Gastrointestinal systems which present in childhood (Fetita 2006). In diabetes the hexosamine pathway is activated and inhibits the pentose shunt pathway which decreases the production of antioxidants and therefore leads to an increase in oxidative stress. This oxidative stress has been found to disrupt gene expression and may contribute to congenital defects. One example is that oxidative stress inhibits a gene called pax-3 which is needed for neural tube closure and in diabetes there is an increased risk of neural tube defects (Horal et al 20

Marketing Analysis of Ecovers Current Position in the Market Essay

Marketing Analysis of Ecover's Current Position in the Market 1. Introduction The assignments mainly consists of the following parts: Firstly, an analysis of Ecover’s current position in the market. Secondly, how Ecover is changing its competitive strategy. Thirdly, consumer behaviour towards detergent. Finally, an outline for new marketing strategy for Ecover to enter the supermarket. 2. Background Ecover was founded in 1979 by Frans Bogaerts.It was a modest little detergent company in Malle in northern Belgium. Pierres Magnin a successful Swiss businessman dealing with pharmacies and health food stores, suggested Bogaerts to develop an eco-friendly detergent free of harmful chemicals (which was to be banned by the Swiss government as a part the proposed environmental regulations). Thus they entered the detergent market in Swiss and other key markets. Environmental disasters have made more and more people aware of the urgent need to protect the natural environment. 3 Marketing Audit Marketing audit give a picture of where the company is, how did it get there and where is it heading. It goes through the through the strength, weakness, opportunities and threat of the company. This analysis is called the SWOT analysis. It is divided into two major parts: External Factors and Internal Factors Strength and weakness are concerned with the internal factors and opportunity and threat are concerned with the external factors. 3.1 External Factors Here only opportunities and threats are analysed as these are supposed to be listed as anticipated events or trends outside the business that have implications for performance. These factors are not controllable by the company. Some of the factors discussed here are: 1.  Ã‚  Ã‚  Ã‚  Ã‚  Macro environment 2.  Ã‚  Ã‚  Ã‚  Ã‚  The Market 3.  Ã‚  Ã‚  Ã‚  Ã‚  Competition 3.1.1Macro Environment Macro Environment consists of Political (P), Economical (E), Social (S) and Technological (T) factors that affect the Company. Continuous monitoring of these variables is an important marketing function. As Corporations today, Ecover is also sensitive to Macro Environmental changes. Some of the PEST factors that affected Ecover are discussed below. Political: Marketing strategy is deeply affected by political trends. Issues like new laws, regulations, change in foreign policies etc brings change to t he bus... ...entalists to recommend its products. 9.Appendix Appendix 1: Survey of consumer attitudes:   Ã‚  Ã‚  Ã‚  Ã‚  Australia  Ã‚  Ã‚  Ã‚  Ã‚  Canada  Ã‚  Ã‚  Ã‚  Ã‚  Germany  Ã‚  Ã‚  Ã‚  Ã‚  Italy  Ã‚  Ã‚  Ã‚  Ã‚  Japan  Ã‚  Ã‚  Ã‚  Ã‚  Holland  Ã‚  Ã‚  Ã‚  Ã‚  Spain  Ã‚  Ã‚  Ã‚  Ã‚  Switzerland  Ã‚  Ã‚  Ã‚  Ã‚   Pay 10-15% more for green products  Ã‚  Ã‚  Ã‚  Ã‚  69  Ã‚  Ã‚  Ã‚  Ã‚  72  Ã‚  Ã‚  Ã‚  Ã‚  68  Ã‚  Ã‚  Ã‚  Ã‚  79  Ã‚  Ã‚  Ã‚  Ã‚  42  Ã‚  Ã‚  Ã‚  Ã‚  87  Ã‚  Ã‚  Ã‚  Ã‚  85  Ã‚  Ã‚  Ã‚  Ã‚  80  Ã‚  Ã‚  Ã‚  Ã‚   Boycott others  Ã‚  Ã‚  Ã‚  Ã‚  82  Ã‚  Ã‚  Ã‚  Ã‚  -  Ã‚  Ã‚  Ã‚  Ã‚  76  Ã‚  Ã‚  Ã‚  Ã‚  79  Ã‚  Ã‚  Ã‚  Ã‚  43  Ã‚  Ã‚  Ã‚  Ã‚  74  Ã‚  Ã‚  Ã‚  Ã‚  86  Ã‚  Ã‚  Ã‚  Ã‚  75  Ã‚  Ã‚  Ã‚  Ã‚   Give up 10-15% quality for environmental safety  Ã‚  Ã‚  Ã‚  Ã‚  65  Ã‚  Ã‚  Ã‚  Ã‚  -  Ã‚  Ã‚  Ã‚  Ã‚  62  Ã‚  Ã‚  Ã‚  Ã‚  80  Ã‚  Ã‚  Ã‚  Ã‚  45  Ã‚  Ã‚  Ã‚  Ã‚  74  Ã‚  Ã‚  Ã‚  Ã‚  64  Ã‚  Ã‚  Ã‚  Ã‚  78  Ã‚  Ã‚  Ã‚  Ã‚   Pay more even if its hard to make end meet  Ã‚  Ã‚  Ã‚  Ã‚  43  Ã‚  Ã‚  Ã‚  Ã‚  -  Ã‚  Ã‚  Ã‚  Ã‚  47  Ã‚  Ã‚  Ã‚  Ã‚  65  Ã‚  Ã‚  Ã‚  Ã‚  46  Ã‚  Ã‚  Ã‚  Ã‚  46  Ã‚  Ã‚  Ã‚  Ã‚  64  Ã‚  Ã‚  Ã‚  Ã‚  64  Ã‚  Ã‚  Ã‚  Ã‚   Source: David Jobber, 1998,Princilpes and practice of Marketing, 2nd Edition. Appendix 2: Table showing Ecover’s competitors ’ market share: Market Share Competitors in Germany& Austria  Ã‚  Ã‚  Ã‚  Ã‚   More than 50% Competitors in Swiss & Germany  Ã‚  Ã‚  Ã‚  Ã‚   Almost 50% P&G and Unilever together (in 1980s)  Ã‚  Ã‚  Ã‚  Ã‚   Almost 80% Private brands (by 1990)  Ã‚  Ã‚  Ã‚  Ã‚   10-30% 10. Bibliography 1. David Jobber, 1998, Principles and practice of Marketing, Second edition. 2.Subash.C.Jain, 1997, Marketing Planning & Strategy, Fifth Edition. 3.Wayne D.Hoyer, Deborah J.Maclinns, 1997, Consumer Behaviour.

Robert Jervis - Perception And Level Of Analysis :: essays research papers

Robert Jervis in Perception and Level of Analysis espouses the notion that in order to fully explain crucial decisions and policies it is essential that one pays heed to the decision-maker’s beliefs about the world and his or her perceptions of others. Rather than attempting to understand foreign policies as directly resulting from the three other levels of analysis, the bureaucratic, the domestic, and the international environment, which he outlines, Jervis contends that examination of a decision-maker’s perceptions, both their causes and effects, can more readily determine and explain behavioral patterns; in such a light, the taxonomy or three other levels of analysis appear devoid of truth value when applied alone, and all related theories are shown as invalid except in extreme cases. Nonetheless, one might more accurately contest that while careful study of a decision-maker’s beliefs is a necessity for comprehension, analysis of such beliefs is in fact an ex amination of bureaucratic organizations, domestic circumstances, and the international environment; all four are interrelated in the sense that the perceptions of the decision-maker are influenced by the circumstances existent in the three other levels. Likewise the three levels are themselves affected and often altered by the politician’s choices. Therefore, in order to provide the most comprehensive explanations of foreign policy decisions one cannot completely disregard externalities, and conversely one cannot ignore individual perceptions of decision-makers. One cannot rely solely on the bureaucratic level of analysis, the domestic, the international environment, or even on a combination of the three as adequate. What one might interpret as a clash of bureaucratic interests and stands yielding incoherent and conflicting policies, could in reality be a â€Å"clash among values that are widely held in both society and the decision-makers’ own minds† (Jervis 28). Similarly, if domestic situations were the medium upon which politicians base their decisions then changes in leadership would not necessarily produce significant changes in foreign policy; however, the consistency of foreign policy is difficult to measure. For example, some might contend that the Cold War would not have occurred had President Franklin Delano Roosevelt not died; they suggest that his death altered American policy in the sense that President Truman and his anti-Soviet position came to dominate political decision-making. Others contest that FDR would ha ve acted similarly to Truman, as he too was coming to an anti-Soviet stance prior to his death. If the former is seen as accurate the domestic level of analysis is insufficient and not applicable, but in the latter instance it could be viewed as a valid basis for judging decision-making.

Guiding Children’s Behavior

I have rated the fourteen steps to guiding children's behavior based on personal belief and experience. 1. Model Appropriate Behavior: Show, demonstrate, model and supervise. Children are watching you therefore you need to be the best role model you can be. As a positive role model you need to make good choices and encourage children to do their best too. It has been proven that children with positive role models have higher self-esteem, do better in school and social settings, and are more likely to make good choices in difficult/stressful situations. Positive role models can last a lifetime. 2. Meet Children's Needs: Children need to eat nutritional foods, drink plenty of water, and get enough sleep and exercise. Children need a safe environment at home and at school. Children need love, affection and respect. Children need to be given opportunities to be successful so they can build self-esteem. Children need to be given responsibility and independence so they can experience self-actualization. As caregivers, it is our responsibility to provide all of these needs, children need us to do this for them. 3. Use and Teach Conflict Management: Teach children how to successfully resolve conflicts. Children need to learn how to handle difficult situations, they don't know how to resolve a problem if we don't show them how. As a role model, it is important to display conflict resolution, children will learn by watching you. It is important to show children how to share, talk it over, take turns, choose to do something else, and say â€Å"sorry†. I think it is so important that adults apologize to children when it's appropriate, respect goes both ways, if you expect a child to say â€Å"I'm sorry† to you then as a role model you should apologize to children when necessary too. . Know and Use Developmentally Appropriate Practice: Learn as much as you can about children, have high but appropriate expectations. As an instructor, it is crucial to always continue learning about Early Childhood Education, stay up-to-date with current methods and trends. 5. Teach Cooperative Learning and Living: This is such an important step because it's a lifetime step. It is crucial to discuss cooperation with children because life is full of social interactions, they need to know how to cooperate in a group settings and how to recognize different behaviors. Talk with children about different behaviors and reactions so they understand how they are feeling and how to react appropriately. 6. Develop a Partnership with Parents, Families, & Others: As an instructor, it is your job to communicate with people who are important in your students life because they are influencing the child outside of the classroom. Make it clear to parents and caregivers that you are always available for communication, that you care about the child and want whats best for them. I think it is extremely important to involve parents and caregivers in classroom activities, they should know what you are teaching and how children are learning. Overall, if there is understanding and communication between parents and teachers then the child will probably have a more rewarding learning experience in the classroom and at home. 7. Empower Children: Children need to learn that they are ultimately responsible for their own behavior, allow children to have choices and support them. It is important that children know you trust their decisions and feel successful when they make positive choices. . Establish Appropriate Expectations: The expectations you have for children should be attainable and used as guideposts in learning. Children should have a clear understanding of rules and limits, this way they know what is expected of them. As an instructor, you should always be clear about exactly what you expect and what the consequences will be if rules and limits are broken. 9. Clarify your Beliefs about Guiding Behavior: It is important to be certain about what you want for children in the classroom and at home. Use a philosophy of education to guide your teaching and review it often, be sure you are always doing your best to do best for the children in your classroom. 10. Use Social Constructivist Approach: Teachers should always be guiding students to behave in a socially appropriate and productive way. Once again, you are a role model, be the best role model you can be, children are watching your decision making and behaviors. Make responsible choices so children can ape this behavior. 11. Help Children Build New Behaviors: Give children praise when necessary. I am a strong believer in the power of positive reinforcement, children react positively when you reward them for making good choices. It is important that children know you recognize they are choosing to make a good choice because it lets them know you are watching them and acknowleding their efforts to control their behavior. 12. Recognize & Value Basic Rights: We all have basic rights, children too! Respect their basic rights and it will be easier to guide and direct children's behavior. 13. Avoid Problems: Positive reinforcement is a great way to focus on good choices and show children that you appreciate their good behavior. Too many times I see parents and instructors who focus on negative behavior and forget to acknowledge positive decision making. If you ignore negative behavior children will learn that they will not get attention or reward for negative behavior. Be sure to always reward and focus on good decision making. Children will learn that by making good choices they will receive praise and rewards. 14. Arrange and Modify the Environment: The classroom should be a safe place of learning and fun. As an instructor, it is your responsibility to provide an annpropriate environment that supports learning for everyone.