It’s up in the Air, or Is It Essay

The article elaborates on how individual sociological imagination can connect social structure to life history. In this case, sociological imagination refers to understanding of individual behavior as the product of historical processes that affects a person’s social environment. The rules of social structure are considered to restrict the conduct of individuals and also mould outcomes for them. However, students are not able to see the connection between individual action and structural outcomes. In sociological imagination, social structural explanation can be used to answer the several questions of social stratification. It is evident that other forces than individual characteristics shape the outcome and distributions of societal rewards (Renzulli, Aldrich, Reynolds, 51). Organizations help to reduce inequality in the society by allowing prospective entrepreneurs from different social origins to access to wealth-generating assets. In order to show how social structure of society shapes the results for individuals, the students can be engaged in a multiple rounds of coin tossing game. The game will also include some rules and regulations to be followed. The results of the game will be highly predictive on how the social structures mould the outcomes of individuals. From the distribution of the coins, the students will realize that inequality and personal prosperity are not the result of personal characteristics (Renzulli, Aldrich, & Reynolds, 56). The alteration of the rules of the game will help the students to see how real world processes generate inequality in the community. It is clearly acknowledged that, structures and rules affect a person’s ability to access an opportunity regardless of his or her talent. However, some improvements have to be done on the game in order to give the best results to the students. Therefore, coin tossing game can be used to effectively demonstrate how sociological imagination increase student understanding of the social world.

Albatross Unit 3 Assignment

Introduction This case mainly deals with the varying types of operational challenges that Albatross Anchor is currently facing. The pricing is not a major issue for the organization and it is able to sell its products at a consistent market rate; however it is unable to realise its full profit potential due to the presence of a lot of operational inefficiencies. It is evident that if the firm is able to overcome all of these challenges, it can make the same level of profits as that of their competitors and can also facilitate their future growth exponentially. We have also analyzed two possible options which can be implemented and have assessed of which may be the most viable option for the company. We have also reached on a conclusion regarding the benefits the company can reap by implementing the strategies in their operational management plan. Question One Based on the information presented in the scenario/case study discuss Albatross Anchor’s competitiveness in relation to (please address all items in the below list and provide support for your conclusions): 1. Cost ) Cost of Production: Due to the presence of operational inefficiencies, Albatross Anchor is unable to reduce their costs as a result of which they have a lower profit margin. Therefore, they have a cost of production disadvantage as compared to their competitors. b) Economies of Scale in material purchasing: They can enjoy Economies of Scale when it comes to purchasing materials. Buying in bulk means they can get discounts from the suppliers on their purchase. c) Co st of Raw Materials Sitting Idle in the Warehouse: The increased amount of goods stored in the warehouse means that Albatross Anchor also needs to incur higher amounts of holding costs of storing the large amounts of inventory. Holding costs refers to the cost of carrying an inventory and may include costs such as, depreciation, deterioration, spoilage, taxes and insurance to name a few. d) Cost of Finished Goods Sitting Idle in the Warehouse: For the international orders the inventory of finished goods stays in the inventory along with the raw materials since the production is only done in small batches. This ultimately increases the holding cost for both the finished goods as well as the raw materials. 2. Speed of manufacturing process from order to finished product. Since the products are produced in limited quantities all the raw materials can be used more effectively. This also reduces the number of complexities during the manufacturing process. Currently their production is strictly dependent on the amount of demand for their products. 3. Flexibility in filling order(s) The manufacturing process is very constrained and is not flexible enough to house the smooth production of two different types of products. Each individual type of anchor requires their exclusive set of manufacturing line and therefore the time required to switch from one mode to another manufacturing mode requires 36 hours; which is quite a long time. 4. Technology The manufacturing process is deprived of new technology, making the process even more painstakingly slow. They are still using the traditional methods of making the anchors. 5. Capacity and facilities The current plan of their facilities is clearly insufficient for managing their operations smoothly. The space for storing the finished goods and the raw materials is located towards the far south of the entire facility and it takes a considerable amount of time and effort to ship the finish goods from there. If the manufacturing area is moved closer to the shipping area; it will save considerable amount of time in shipping these finished products. The foundry is not a part of the manufacturing department which further impairs the smooth flow of work in the production process. If the foundry is moved towards the manufacturing process it may increase the firm’s ability to cater to international orders more quickly. For having a mixed model of manufacturing process the Focused Factory process can be used. The Focused Factory aims for a narrow range of products and processes; as a result these factories are also small and quite simple and focus on only one or two products. 6. Service to customers Currently Albatross Anchors only sell their products through OEM customers and to the distributors. Apart from this, their products are of superior quality and are available to the customers in two varied forms. This not only gives Albatross Anchors greater choice, but also ensures that it leads to greater customer satisfaction. However, due to its current operational management procedures it is unable to reap the benefits of it as compared to their competitors. Question Two There are many ways that mushroom/bell anchors may be manufactured. Albatross Anchor is considering two new manufacturing processes (Process A and Process B) to reduce costs. Analysis of the information below will help determine which process has the lowest breakeven point (this validates the process is more cost effective). For each process the following fixed costs and variable costs are identified below: Anchor and Process| Process A| Process B| Sale price per anchor| $45. 00| $45. 00| Total Fixed cost | $ 650,000. 00| $950,000. 00| Variable cost per anchor| $ 36. 00| $ 29. 99| Based on the information in the table above complete the table below: Anchor and Process| Process A| Process B| (a) Fixed costs per anchor|   $9| $15. 01  | (b) The total number of anchors to attainbreak–even point for Process A and Process B|   72,222 units|   63,291 units| (c) Based on your calculations which Process (A or B) that you would recommend for adoption (you can select only one). Please make sure to explain how you arrived at your conclusion. Ans. (a)   At Break Even Point: Total revenue = Total cost i. e. p*x = v*x + F                        where, p = Sales Price per Anchor v = Variable Cost per Anchor                                       F = Total fixed Cost x = Total Anchors to be manufactured for Break Even. Since, p*x = v*x + F => (p-v)*x = F => (p-v) = F/x i. e. (p-v) = Total fixed cost per Anchor Now             Total fixed cost per anchor for Process A = (pA -vA) = (45-36) = $9 per Anchor                        Total fixed cost per anchor for Process B = (pB  -vB) = (45-29. 99) = $15. 01 per Anchor Ans. b)   (p-v)*x = F =>          x = F/(p-v)                                 Number of units to be manufactured at break even For Process A: xA = FA/(pA-vA) = 650,000/ (45-36) = 72,222. 22  ? 72,222 units to be manufactured at break even. For Process B: xB  =  FB/(pB-vB) = 950,000/ (45-29. 99) = 63,291. 14  ? 6 3,291 units to be manufactured at break even. Ans. (c)  Process B should be adopted for two reasons: (1) The break-even point for process B is 63291 units which is less than that                                 of process A at 72,222 units, so process B is more cost effective. 2) Process B is also better than Process A in terms of the Operating leverage which can be defined as the change in net income per unit increase in sales volume. Mathematically, operating leverage can be written as follows:                            Operating Leverage = F/(vx*)   where x*  is units to be manufactured at Break Even point. Operating leverage for process A = 650,000/(36*72222) = 0. 25                Operating leverage for process B = 950,000/(29. 99*63291) = 0. 5                Therefore the process B is also better in terms of the operating leverage as opposed to process A. Conclusion Although Albatross Anchors produces only two types of products; it has huge growth potential which still remains untapped. They can surely achieve more than their current growth rate. They can also undertake other important initiatives which can significantly increase their competitiveness. For instance, product diversification, improved operational processes, and greater employee satisfaction may all contribute in increasing their success in marketplace and further fuel their productivity. As clearly evident from the calculations, implementation of process B in the company can prove to be quite fruitful.

Young Goodman Brown Analysis

The gloom Young Goodman Brown is feeling from the truth he discovers during the night is completely justified. How could it not be after such a traumatic experience? His entire image of the world around him was shattered. The people he new and looked up to, were not what he spent his life believing them to be. There are many passages by Young Goodman Brown that portray these thoughts, feeling, loss of innocence, and changes to his perception in the short story by Nathaniel Hawthorne. What immediately stood out to me was the sweet exchange of words Goodman and Faith had, at the train station before his departure.Faith had bad dreams and negative thoughts about Goodman’s trip and does not want him to leave. Goodman replies, â€Å"My love and my Faith, of all nights in the year, this one night must I tarry away from thee. † This line was the best. I have never heard a better way to tell a woman that I can not spend time with her. This line will be used by me at some time i n my life. I wonder how much better Goodman’s life would have been if he would have listened to faith. Goodman regarded Faith as his anchor to everything that is right in the world.Faith, with her pink ribbons, is what could right any of the wrongs that might happen to him on his trip. â€Å"After this one night I’ll cling to her skirts and follow her to heaven,† he tells himself in the fashion of a silent prayer, pleading to make it through the night. I see this concept, of using Faith as a prayer, when he meditates on the phrase, â€Å"what calm sleep would be his that very night, which was to have been spent so wickedly, but so purely and sweetly now, in the arms of Faith! Amidst these pleasant and praiseworthy meditations. † It seemed as if everyone from the village had a relationship with the devil.â€Å"I helped your grandfather, the constable, when he lashed the Quaker woman so smartly through the streets of Salem: and it was I that brought your f ather a pitch pin knot, kindled at my own hearth, to set fire to an Indian village, in King Philip’s war,† said the devil. One of the first moments of truth occurred when Goodman witnessed Goody Cloyse speaking to the devil. Hawthorne portrays Goodman’s shock by having him repeat the phrase, â€Å"That old woman taught me my catechism. † Once you start on the road of behavior that makes you lose your innocence, the easier it becomes to travel down that path.The devil said, trying to comfort Goodman, â€Å"You will think better of this by and by. † The moment the Devil plucked the maple branch and it withered was a metaphor of how evil corrupts the innocent and a representation of what was in store for Goodman’s life after that night. Goodman was so shocked that the very leaders of his faith, the Deacon, would venture out into the night to meet the man with the snake cane. Then Goodman heard the cry of grief and held the pink ribbon in his han d crying out, â€Å"my Faith is gone,† was the end of his trying to withstand the devil.He gave up stating, â€Å"there is no good on earth; and sin is but a name. † In this moment of despair he calls out to the devil stating, â€Å"Come, devil; for to thee is the world given. † When he felt he lost is anchor (Faith) to everything that was Holy and pure to him he gave up. In Goodman’s mind he had no other choice to follow the Devil and after being apart of that ritual of initiation and the devil’s sermon, there was no coming back for him. Young Goodman Brown will forever be gloomy and withdrawn.

Letter Essay Example | Topics and Well Written Essays - 250 words - 20

Letter - Essay Example In the research paper, I will argue that the increasing fire outbreak cases in America are as a result of poor or lack of effective measures vital in preventing and dealing with fire outbreak cases. Ultimately, the cases of fire have had a detrimental impact on the safety of individuals and the economic growth of the country. The research paper will incorporate issues like fire prevention, the prevention of rapid spread of fire as well as the provision of resources including fighting equipment in the outbreak of fire. Consequently, I will dwell on the safety of individuals in the case of outbreak. To carry out my research, I will utilize various resources including periodicals, books and the internet as well as case studies relevant to the topic to decipher critical and vital information in relation to current statistics and cause for the predicament. I am particularly aware that it is unethical to utilize someone else’s work and ideas as my own as this will be an act of plagiarism, therefore, throughout my research on fire safety issues, I will utilize proper APA citation as per the project

Comparison and Contrast of Kukaniloko Birthing Stones and Queen's Essay

Comparison and Contrast of Kukaniloko Birthing Stones and Queen's Medical Center Birthing Unit - Essay Example She had to follow a strict diet and do exercises recommended by the Kahuna. Only green vegetables, herbs and a small amount of raw fish were allowed. After six months she was asked to eat less because of the fear that a large baby will be difficult to deliver. Many relatives gathered on the delivery day. 36 chiefs eye witnessed the ceremony and birth. The mother was taken to Kukaniloko birthing stone on a woven rug. She was encouraged to walk to increase the pain. She then took kneeling position. It was gravity type birth. She was given morning glory leaves to eat. Some were also rubbed on her stomach. After delivery placenta was buried under tree. Mother was given herbs and soup (Empleo, 2012). There are many similarities between Queens Medical Center’s birthing unit and Kukaniloko Birthing Stones in Wahiawa, Hawaii. Women in Kukaniloko used to give delivery in kneeling position and they had to do exercises recommended by Kahuna. Queens Medical Center encourages women to have upright position like squatting and kneeling. They also recommend exercise during pregnancy which helps in easy delivery. . Ultrasound is done to determine the position of baby. In Kukaniloko mother was monitored many times during pregnancy. Nowadays pregnancy is monitored by the use of ultrasound which is equivalent to the monitoring practice that was witnessed in Kukanilolo. Despite the similarities, quite a number of differences exist. Early skin-to-skin contact is recommended in Queens Medical Center. It is believed that skin-to-skin contact between mother and baby reduces crying and creates bonding. Breastfeeding is given a lot of importance ("Breastfeeding: The First Weeks at Home",  n.d.). Breastfeeding is beneficial for both the mother and the baby. While in Kukaniloko the baby was taken away by a nurse who was called "kahu". The kahu fed the child. As far as the environment is concerned, a number of aspects need to be covered

The Canterbury Tales Writing Assignment Essay Example | Topics and Well Written Essays - 1000 words

The Canterbury Tales Writing Assignment - Essay Example Later on, the Miller’s Tale tells a rather lustful and vulgar story of a Carpenter and his wife who deceives her husband with a clerk. Overall, the loathsome and vulgar character of the Miller surpasses the aversion of other characters from The Canterbury Tales. The Miller’s Tale effectively illustrates the lecherous personality of the Miller who narrates a lewd story of a carpenter named, John and his wife, Alisoun. John, who works as a carpenter rents out a room of his house to a student named Nicholas. Another clerk named Absolon is also there in town who later falls in love with Alisoun. The story exhibits a high degree of deception where Alisoun becomes involved with Nicholas as well as Absolon at the same time while her husband leaves town for a few days. At another occasion, Nicholas fools John of a deluge of the same intensity as that of Noah’s time. John climbs into a basket to save himself from the flood while Nicholas and Alisoun are spending time toge ther in their bed. At the same time, Absolon arrives and brands Nicholas upon which he cries â€Å"Water!† (Chaucer 3815). Upon hearing this, John cuts the rope to his basket and falls down. The townspeople arrive at the scene and laugh at John. The whole story of the carpenter’s wife, Alisoun cheating her husband by having an affair with two younger men at the same time represents an indecent and boorish side to the personality of the Miller. Thus, this example suggests the lecherous internal character of the Miller apart from his already obnoxious physical outlook. The Miller is a character possessed not only by a vile internal nature but also an outrageous physical character. The detail regarding the Miller’s activities and interests build on to his strong and physical personality. In the prologue, Chaucer introduces its readers to the Miller’s most regular practice of wrestling where he always wins the ram (548). His ability to break doors with his he ad (Chaucer 550-551) and the wrestling matches he has won demonstrate his strong physical capabilities adding on to his huge and disgusting outlook. Further details of his appearance reveal his unappealing outward image that makes him an ugly individual. The descriptions of ugly features including his red beard, huge physique, wart with tufts of hair, and huge dark nostrils display a repulsive character that conjures up horrific images in the mind of the readers. As a person closely observes the explanation of the Miller’s personality, it is not hard to picture a disgusting character with repulsive features that is dishonest and vulgar by nature. During his conversation with the Host prior to the narration of his tale, he announces that he is drunk and that he should be forgiven in case he says anything wrong. When he goes on to tell his tale, his story points out the immoral side of wives. The Miller’s huge personality along with his red beard and hairy wart represent a coarse side to the character of the Miller who although has a large physique but little intelligence. Apart from the Miller’s rude and ribald inclinations, he is also a dishonest man in his business. The Miller is not only a lustful and physically disgusting character, but also a dishonest man who tricks his customers by stealing corn or getting them to pay more (Chaucer 562). With the huge

Medical Care in the United States Assignment Example | Topics and Well Written Essays - 500 words

Medical Care in the United States - Assignment Example That said, the cost of providing that care that falls upon the government will always be a consideration and cannot be disregarded. Finding a balance that is pleasing both to the healthcare need and to the country’s costs will be extremely difficult to achieve. A solution that will be successfully pleasing to all parties involved will be even harder. There will always be a level of imbalance present given the numbers of Americans who are financially unable. This will leave a perpetual area of imbalance in the need for and the economics of healthcare. The healthcare system that currently exists is definitely flawed and positive change can only benefit the country. However, unless the replacement is more functional and provides better outcomes for both the application of the healthcare system and economic cost to the country than the changing would be expensive to implement to have little change and therefore pointless results. Obamacare is hugely different from what Americans a re currently accustomed to in that it will require individuals to obtain health insurance or be fined for not doing so at tax time. Americans will find that insurance costs will rise. The cost will be even higher for Americans with pre-existing conditions previously denied by insurance companies. Again, I am not saying the reforms are not in order or that Americans do need to take a more responsible role in their own healthy living and healthcare, but Obamacare is simply not the reform that will succeed in the United States.

Lobbyists Essay Example | Topics and Well Written Essays - 1000 words

Lobbyists - Essay Example Lobbying is therefore, the practice of promoting, opposing, or in any manner influencing or attempting to influence the introduction, defeat, or enactment of legislation before any legislative body; opposing or in any manner influencing the executive approval, veto, or amendment of legislation. It is also the practice of promoting, opposing, or in any manner influencing or attempting to influence the enactment, promulgation, modification, or deletion of regulations before any regulatory body (Smith). A lobbyist is therefore a term that includes the following; a person who receives compensation from another person, group or entity to do the lobbying work. A lobbyist is also the person who lobbies as a regular and usual part of employment irrespective of whether there is compensation in addition to regular salaries and benefits is received. a lobbyist is also the a consultant to the state, county, or municipals parts of the government, they are employed to make an influence legislation or regulations irrespective of whether they are paid or not; in full or in part the funds that relates to these forms of government (Luneburg, William, and Susman). Lobbying is quite an important act given the experience they give to the Lobbyist groups. From research it is clear that experienced and successful lobbyists extensively understands the legislative process and therefore they have a strategic plan which enables them to ensure a close follow up that is quiet significant to the client or group that they present. The understanding of the process is quite complex due to the increased competition of the recent past in the field. Lobbying through the Lobbyists helps the congress to follow issues in a timely manner making issues to be handled quite in time due to the avoidance of the delay likely to be created. This is driven by the fact that opportunities and challenges often present themselves with quite a short time to respond to such allegations prompting the need for lobby ing and lobbyist groups. Ongoing, active representation in Canadian legal departments is critical to effectively responding to these situations (Luneburg, William, Thomas, Susman, and Gordon). Lobbying is therefore meant to help specialists groups which may be of a special religion, belief or industry to get their voices to be heard by members of any law making body of a nation. In addition, lobby groups of large amounts of money are able to influence the opinions of the crowds in their favor making politicians against them vulnerable (Smith). Currently, Lobbying has become a way for corporations, religions, and other private and special interest groups present their influence over the legislature and essentially circumvent the standard law-making procedure. Lobbying is therefore protected by the model of government in place and since corporations and other special interests are legally considered a singular entity, they are represented in the same context in Congress (Smith). The d ata from the office of the Commission of Lobbying of Canada shows us the various lobbying groups that exists in

Human Resource issues at Amazon Coursework Example | Topics and Well Written Essays - 4500 words

Human Resource issues at Amazon - Coursework Example Within the warehouses the houses a mix of 1600 full-time part-time and temporary workers. Most of the temporary workers are hired by the company before the holiday season and fired after that period. The task designed to most of the labours inside the warehouse is to pack boxes. The warehouse is located over an area of 600,000 square foot. Inside these warehouses, the workers are required to pack boxes at the rate of 240-250 boxes per hour if the size of the shipment is large and up to 500 boxes per hour are the size of the shipment is small. In comparison to other companies in the same industry, this rate is excessively high. Amazon, as it is found, sets the rates higher than can be performed by the employees. It is expected even by Amazon that people won’t be able to attain the high productivity rates for which there are paid between $9 and $14 an hour. The workers are expected to work for 10 hours a day for four days in a week. In the holiday season when the shopping spree of the customers increases Amazon recruits temporary workers who have to work for 11 hours per day for four days in a week along with the regular staffs. The overtime in the holiday period is mandatory for the workers. The workers are given a 30-minute lunch break for which they are not paid. In addition, they are given two paid breaks each of the duration of 15 minutes. During the break, every minute is counted and the workers have to take a break at the ring of the bell and have to be back at their work at the ring of another bell.

Business of Being Born Essay Example for Free

Business of Being Born Essay There is a culture of â€Å"women-only† that runs rampant in spaces for pregnant women. Much of the talk is about how valuable women find the support of other women. It also excludes men from the process and experience of pregnancy, as much as they can experience it. Overall the film focuses on the fact that women have been told they’re not responsible for their birth. Katsi Cook, a Mohawk women and Native women’s health activist said she â€Å"believes that the relationship of trust and respect between a woman and her midwife empowers the woman to ask questions and obtain the information she needs to make real choices about her health and life. (The Mother’s Milk Project, 611) In the film, Ricki Lake wanted to explore women’s â€Å"rite of passage,† by giving the power back to the women. There’s this idea since hospitals are a business that once they â€Å"facilitate† an intervention has been started and it becomes a domino effect after that. When these interventions have started, the questions: â€Å"what’s best for the baby? † â€Å"Is the baby going to benefit from this or not? † need to be well thought out. According to Overview of Maternity, â€Å"medical evidence shows that the routine use of unnecessary interventions put mothers and babies at risk. In the film Marsden Wagner M. D. , stated that there is no history of worthy obstetrical practices and careful studies of the long-term effects of the interventions. The United States has gotten away from midwifery starting in 1955, only 1% of births took place at home. The culture shift portrayed midwives as â€Å"vestige of the old country. † Midwives were understood as dirty, ignorant and illiterate. Now midwives are often perceived as unprepared. Once doctors started graduating from medical school, business took over the birthing process. Births then went into the hospitals and midwives did not follow. The concept of normal changed. Midwives often lack available and affordable malpractice insurance; because of this midwives are then perceived â€Å"inferior† to physicians. Overview of Maternity states â€Å"Midwives recognize birth as a normal, natural process and support the use of less invasive techniques, such as position changes, waiting, hydrotherapy, and perinatal support, that carry fewer risks to mothers and babies and are usually more effective. † Another effect the culture has on the lack of midwives is when the culture as a whole insinuates that birth s scary and dangerous. Yes, there will always be some sort of risks when it comes to birth. However, that is where I believe technology has had a positive effect on birth. More than less, we are now able to detect the dangers ahead of time. The film associates the amount of trust we put into hospitals and technology is reflected upon our infant-mortality rate. Our neonatal statistics are not the greatest. In the film midwives and hospitals are not looked to blame. It is our diverse population that distorts those statistics in where we stand in the world. The argument presented in this film to revitalize midwifery focused generally on the idea of pain suffered during birth was the only way to feel accomplished and provide love for their baby. However, I completely disagree. Women that undergo C-sections and even families that adopt can have the same amount of love for their children as the women that endure pain during birth do. Normal births are not medical issues, yet they may turn into life threatening issues within seconds. Not all women are the same, they have different difficulties, and some even have disabilities that impact their birthing process. Which then increases the risks. According to Overview of Maternity, â€Å"Research shows that midwives are the safest birth attendants for most women, with lower infant and maternal mortality rates and fewer invasive interventions such as episiotomies and surgical births (cesareans). † Optimum outcome of the mother and child is based on how open to suggestions we are with midwives and patient satisfaction. The validity of your options must always be questioned. The safety of the birthing process is going to vary depending on the training, patient choice, and circumstances on geographical constraints.

Idiopathic Inflammatory Myopathies (IIMs)

Idiopathic Inflammatory Myopathies (IIMs) 1.1 Introduction to IIMs Idiopathic inflammatory myopathies (IIMs) are a group of rheumatic disorders affecting skeletal muscle, they are thought to be auto immune in origin (Rothwell et al., 2013), but as their name implies the actual cause remains something of an enigma. The phenotype of IMMs is generally characterised by progressive symmetrical proximal muscle weakness and rapid fatigue, MHC class 1 expression in muscle fibres (van der Pas et al., 2004), increased circulating muscle enzymes (Creatine kinase, lactate dehydrogenase)(Cox et al., 2010), and the invasion of inflammatory infiltrates such as immune cells and cytokines (Lundberg et al., 1997; Grundtman et al., 2007). They are heterogeneous in their clinical presentation with patients displaying differing histopathological features, and exhibiting varying disease durations and treatment responses; this is probably associated with the numerous genetic and environmentally implicated factors that have been recently discovered (Rothwell et al., 2013). Interestingly, overt muscle atrophy is not a typical feature of IMM as it is in most diseases associated with muscle fatigue. Inflammatory infiltrate presence in muscle fibres is indicative of cytotoxicity (Lundberg et al., 1997). However, it is often observed that the extent of infiltrate presence in the muscle fibre does not often correlate with the degree of muscle dysfunction (Grundtman et al., 2010), implying that impaired muscle performance is the result of something other than muscle cell damage induced by inflammatory cells and their products; and the continued progression of pathology in the absence of infiltrates suggests that the muscle itself could be contributing. Furthermore, it has been found that weakness can in-fact precede infiltrate presence, and in immune-suppressed individuals weakness can persist (Lundberg Chung, 2000). Muscle weakness is usually initiated in the large muscles around the hips and shoulders, but often spreads to more distal areas resulting in quadriparesis (weakness in all four limbs) that can be severely debilitating. The impact of this can cause the patient difficult y in carrying out even simple everyday tasks such as climbing stairs and can be particularly dangerous in older patients who often have related morbidities. As the disease progresses, eventually the patient’s fine motor skills can be impeded: distal muscle action is required for these movements and weakness in these regions can have affect fine motor skills (Dalakas, 1991). Dysphagia (difficulty swallowing) is also common in severe cases and can cause fatal choking. IMMs clearly have an adverse impact on the patient’s quality of life, and a deeper understanding into the disease is essential for this to be improved. However, some patients are only mildly affected; this heterogeneity makes it difficult to establish the definitive cause of myositis, and treatment is therefore limited. IMMs can be subdivided into three main discrete histological categories: Polymyositis, Dermatomyositis, and Inclusion Body Myositis. 1.2 Dermatomyositis (DM) DM is a microangiopathy that affects both the skin and muscle tissue, and is caused by the lysis of endomysial capillaries and muscle ischemia (Dalakas Hohlfeld, 2003). It was Hohlfeld that described the criteria for diagnosing IMMs; a diagnosis can be made subsequent to three laboratory experiments: serum muscle enzyme concentrations, electromyography, and muscle biopsy (Dalakas Hohlfeld, 2003), and in some cases a skin biopsy may be useful in diagnosing DM. Creatine Kinase (CK) elevation is the main indicator of DM, and is usually correlative to disease severity. It is common for skeletal muscle CK concentration to increase fifty-fold in patients with active DM, but in some patients levels remain basal (Dalakas Hohlfeld, 2003). The muscle biopsy is critical for an accurate diagnosis and would generally show perifascicular atrophy caused by phagocytosis and necrosis of the muscle fasciculus; this is diagnostic of DM even in the absence of inflammation. CD4 positive T-cells are us ually detected in the dermis at sites of perivascular inflammation, and capillary density is dramatically reduced with vessel perforation. DM was unsurprisingly the first to be reported in 1875 by Potain (Potain, 1875) (Oddis Medsger Jr, 1995), probably due to its extramuscular manifestation of heliotrope (upper eyelids), and erythematous (face, neck, back, shoulders) rashes that commonly precede muscular weakness (Dalakas Hohlfeld, 2003). The extensor joint surfaces of DM sufferers are commonly covered in Gottrons papules, along with dilated capillary loops at the base of the finger nail with thickened cuticles (Dalakas Hohlfeld, 2003). The outward appearance of DM often leads to a false diagnosis of systemic lupus erythematosus as muscle weakness is not always evident in DM patients; however, the two diseases differ in that only the latter involves a phalangeal rash. DM has been shown to be the most common form of juvenile myositis, though there have been reported rare incidences of polymyositis (Sato et al., 2000). If treated early on, DM has been shown to respond to immunotherapeutic agents; however, the first line of treatment is usually corticosteroids such as high-dose oral Prednisone. Patients usually show some degree of response to steroid treatment alone, but they are usually administered in conjunction with other immune targeted treatments (Aggarwal Oddis, 2012). 1.2 Polymyositis (PM) In 1887 Unverricht reported the first case of PM (Unverricht, 1887), which presents without the classical rash associated with DM. It is the least common form of myositis and onset is almost universally after 18 years of age, though as previously mentioned it has been reported in the juvenile form (Sato et al., 2000). Epidemiology of PM is difficult to quantify due to it being a rare form of a rare disease that was for many years indistinguishable from Inclusion Body Myositis. PM develops slowly over months or years, and identifying the exact, or even approximate, time of onset is difficult due to the progressive nature and lack of the characteristic rash associated with DM. Muscle weakness progresses in much the same way as DM and is equally as debilitating (Dalakas Hohlfeld, 2003). Diagnosing PM generally involves the exclusion of other similar myopathies using the three diagnostic laboratory experiments described earlier. In PM, unlike DM, CK concentration is always elevated significantly above the basal level. CD8-positive T-cells are found to be invading healthy muscle fibres expressing MHC class I antigens forming a CD8/MHC-1 complex (Dalakas Hohlfeld, 2003). There has long been evidence to suggest that PM could be induced by viral infiltration, possibly via retro-viral infection (Dalakas et al., 1986). The treatment approaches for PM are the same as DM, and in about 70% of patients intravenous immunoglobulin appears to be a promising treatment. 1.3 Inclusion Body Myositis (IBM) IBM was not universally accepted as a separate classification to DM and PM until 1978 (CARPENTER et al., 1978), but it has since been found to be the most common acquired IMM in the elderly, and in men over the age of fifty (Dalakas Hohlfeld, 2003). There are two types, sporadic- and hereditary-IBM, the two are histologically and ultrastructurally similar, but hIBM lacks inflammation. IBM was pathologically characterised by Yunis and Samaha, who coined the term in 1971 (Yunis Samaha, 1971); they noted in patients the presence of vacuoles containing cytoplasmic degradation products with fibrillary nuclear and cytoplasmic inclusions that distinguished IBM from PM, something it is often misdiagnosed as. Insoluble amyloid protein deposits are also found in the muscle tissue of IBM patients, along with the invasion of CD8/MHC-1 complexes that are also associated with PM, and perivascular and endomisial inflammatory infiltrates (Grau Selva-O’Callaghan, 2008). CK levels are usuall y, but not always, elevated slightly. The vacuoles associated with IBM are indicative of muscle atrophy, something that is not generally seen in DM or PM. The process is gradual, occurring slowly over years similarly to many muscular dystrophies. In PM patients that do not respond to therapy, a diagnosis of IBM is now generally considered. Most IBM patients do not show a marked response to anti-inflammatory or immunosuppressant therapy; a few, probably those with an early diagnosis, show a limited response to corticosteroids, and cytotoxic drugs, but this is not always sustained. Exercise therapy is often suggested to stabilize muscle strength and function, and is frequently advised (Grau Selva-O’Callaghan, 2008). 1.4 Epidemiology Onset of myositis is most common in adults and is generally sporadic, though it has been postulated that there could be some underlying genetic predisposition that could attribute to myositic presentation in some individuals (Cox et al., 2010; Rothwell et al., 2013). Juvenile myositis is less common than the adult form, with dermatomyositis being most prevalent (Dalakas Hohlfeld, 2003); it’s incidence creates discrete age brackets in which IIMs occur. IIMs are regarded as rare, and though there have been numerous attempted epidemiological studies they generally have a low sample size, and it is therefore difficult to determine accurate statistics; also, most statistics are no longer accurate as the old classification of IMMs (Bohan and Peter) could not distinguish between Polymyositis and Inclusion Body Myositis. IMMs have been shown to be most prevalent in women, with DM being the most common diagnosis (Dalakas Hohlfeld, 2003). 1.4 High Mobility Group-box 1 Protein (HMGB1) HMGB1 is a non-histone chromatin associated protein; under typical physiological conditions it is confined within the nucleus where it regulates an array of important transcriptional pathways by binding to and distorting sections of DNA, allowing for the assembly of multi-protein complexes (Bianchi Manfredi, 2004). In response to tissue damage, the normally nuclear protein translocates to the extracellular space and acts as an inflammatory cytokine. Excessive cytokine signalling by HMGB1 has been shown to be fatal in mice (Wang et al., 1999). However, it has been observed that in models of tissue regeneration HMGB1 acts as a chemotactic agent to recruit stem cells such as mesangioblasts in vitro, which indicates it has an in vivo role of favouring muscle regeneration by promoting vessel formation (Vezzoli et al., 2011) (Sachdev et al., 2013). It is therefore interesting that it’s implicated role in IMMs is pathological. 1.5 HMGB1 in IIMs When activated by inflammatory stimulants, HMGB1 is actively secreted from monocytes and macrophages via specialised organelles such as secretory lysosomes (Bianchi Manfredi, 2004); HMGB1 is found to be significantly elevated in patients with IIMs (Grundtman et al., 2010). This translocation is permitted by the hyperacetylation of lysines on HMGB1 (Bonaldi et al., 2003) allowing it to be permanently dissociated from the chromatin, and become packaged in secretory lysosomes. In necrotic cells the cellular membranes lose their integrity and soluble proteins such as HMGB1 are allowed to leak out; this differs from apoptosis where the cell death is not signalled by this leak as HMGB1 remains tightly bound to the chromatin (Bianchi Manfredi, 2004). Necrosis is thought to be the predominant route for cell death in IIMs (Schneider et al., 1996); this allows for HMGB1 to be passively released from the cell. HMGB1 exists in mutually exclusive redox forms that mediate specific inflammatory roles (Venereau et al., 2012). Full reduction of Cysteines 23, 45, and 106 occurs initially, forming all-thiol-HMGB1; in this state it has a cytokine stimulating activity. It is thought that this is the form secreted by activated monocytes to help contribute to the inflammatory response. Later, a disulphide bond forms between C23 and 45 in the HMG-BoxA domain of HMGB1 whilst the Box B C106 remains unpaired and in the thiol state (Venereau et al., 2012). The disulfide form possesses chemoattractant capabilities, causing the migration of leukocytes to the region of inflammation (Venereau et al., 2012). Only the fully reduced form can recruit motile cells, making the cytokine stimulating and chemoattractant activities of HMGB1 also mutually exclusive. Terminal oxidation of HMGB1 fully abrogates its bioactivity, but slight oxidation is required to convert all-thiol HMGB1 to disulphide-HMGB1; it is thought that infiltrating inflammatory cells cause the conversion by maintaining the extracellular oxidative environment as they are a well characterised source of reactive oxygen species (ROS). HMGB1 is a ligand for the Toll-like Receptor 4 (TLR4), a mediator of the innate immune response; though it is found in both healthy individuals and myositis patients, it is proposed to be the receptor for which muscle dysfunction in IIMs is mediated (Zong et al., 2013). The TLR4 plays an important role macrophages and monocytes where it is involved in pathogen recognition. Patient data from a recent study suggests that HMGB1 may induce MHC class 1 expression in patients with IIMs via activation of the TLR4: MHC class 1 and TLR4 have been found to be coexpressed in the muscle fibres of patients with myositis but not healthy individuals (Zong et al., 2013). Another receptor through which HMGB1 signals is the Receptor for Advanced Glycation Endproducts (RAGE); an in-vitro knock out study using intact single fibres demonstrated that HMGB1 acts via the TLR4 and not RAGE to induce muscle MHC class 1 expression and fatigue by decreasing the Sarcoplasmic Reticulum (SR) Ca2+ released by actio n potentials (Zong et al., 2013). However, this may not necessarily be true in-vivo. Nevertheless, the HMGB1-TLR4-MHC 1 pathway seems to be an integral part of the pathogenesis of IMMs and could therefore be a potential therapeutic target. It has been shown that aerobic exercise (a common and beneficial intervention for IIM patients) reduces TLR4 mRNA in skeletal muscle of rats (Zanchi et al., 2010), thus further suggesting that TLR4 plays a key role in IMMs. References Aggarwal R Oddis CV. (2012). Therapeutic advances in myositis. Current opinion in rheumatology 24, 635-641. Bianchi ME Manfredi A. (2004). Chromatin and cell death. Biochimica et Biophysica Acta (BBA) Gene Structure and Expression 1677, 181-186. Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, Rubartelli A, Agresti A Bianchi ME. (2003). Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. The EMBO Journal 22, 5551-5560. CARPENTER S, KARPATI G, HELLER I EISEN A. (1978). Inclusion body myositis A distinct variety of idiopathic inflammatory myopathy. Neurology 28, 8-8. Cox S, Limaye V, Hill C, Blumbergs P ROBERTSà ¢Ã¢â€š ¬Ã‚ THOMSON P. (2010). Idiopathic inflammatory myopathies: diagnostic criteria, classification and epidemiological features. International journal of rheumatic diseases 13, 117-124. Dalakas M, London W, Gravell M Sever J. (1986). Polymyositis in an immunodeficiency disease in monkeys induced by a type D retrovirus. Neurology 36, 569-572. Dalakas MC. (1991). Polymyositis, Dermatomyositis, and Inclusion-Body Myositis. New England Journal of Medicine 325, 1487-1498. Dalakas MC Hohlfeld R. (2003). Polymyositis and dermatomyositis. The Lancet 362, 971-982. Grau JM Selva-O’Callaghan A. (2008). Sporadic inclusion body myositis. In Diagnostic Criteria in Autoimmune Diseases, pp. 165-168. Springer. Grundtman C, Bruton J, Yamada T, Ãâ€"stberg T, Pisetsky DS, Harris HE, Andersson U, Lundberg IE Westerblad H. (2010). Effects of HMGB1 on in vitro responses of isolated muscle fibers and functional aspects in skeletal muscles of idiopathic inflammatory myopathies. The FASEB Journal 24, 570-578. Grundtman C, Malmstrà ¶m V Lundberg IE. (2007). Immune mechanisms in the pathogenesis of idiopathic inflammatory myopathies. Arthritis research therapy 9, 208. Lundberg I Chung Y-L. (2000). Treatment and investigation of idiopathic inflammatory myopathies. Rheumatology 39, 7-17. Lundberg I, Ulfgren AK, Nyberg P, Andersson U Klareskog L. (1997). Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies. Arthritis Rheumatism 40, 865-874. Oddis CV Medsger Jr TA. (1995). Inflammatory myopathies. Baillià ¨res clinical rheumatology 9, 497-514. Potain P. (1875). Morve chronique de anormal. Bull et Mem Hop Paris 12, 314-318. Rothwell S, Cooper RG, Lamb JA Chinoy H. (2013). Entering a new phase of immunogenetics in the idiopathic inflammatory myopathies. Current opinion in rheumatology 25, 735-741. Sachdev U, Cui X Tzeng E. (2013). HMGB1 and TLR4 mediate skeletal muscle recovery in a murine model of hindlimb ischemia. Journal of vascular surgery 58, 460-469. Sato M, Bando T, Hasegawa S, Kitaichi M Wada H. (2000). Recurrent spontaneous pneumothoraces associated with juvenile polymyositis. CHEST Journal 118, 1509-1511. Schneider C, Gold R, Dalakas MC, Schmied M, Lassmann H, Toyka KV Hartung H-P. (1996). MHC Class l-Mediated Cytotoxicity Does Not Induce Apoptosis in Muscle Fibers nor in Inflammatory T Cells: Studies in Patients with Polymyositis, Dermatomyositis, and Inclusion Body Myositis. Journal of Neuropathology Experimental Neurology 55, 1205-1209. Unverricht H. (1887). Polymyositis acuta progressive. Zeitschrift fur Klinische Medizin 12, 533. van der Pas J, Hengstman GJD, ter Laak HJ, Borm GF van Engelen BGM. (2004). Diagnostic value of MHC class I staining in idiopathic inflammatory myopathies. Journal of Neurology, Neurosurgery Psychiatry 75, 136-139. Venereau E, Casalgrandi M, Schiraldi M, Antoine DJ, Cattaneo A, De Marchis F, Liu J, Antonelli A, Preti A Raeli L. (2012). Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. The Journal of experimental medicine 209, 1519-1528. Vezzoli M, Castellani P, Corna G, Castiglioni A, Bosurgi L, Monno A, Brunelli S, Manfredi AA, Rubartelli A Rovere-Querini P. (2011). High-mobility group box 1 release and redox regulation accompany regeneration and remodeling of skeletal muscle. Antioxidants redox signaling 15, 2161-2174. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S Borovikova L. (1999). HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248-251. Yunis E Samaha F. (1971). Inclusion body myositis. Laboratory investigation; a journal of technical methods and pathology 25, 240. Zanchi NE, Lira FS, de Siqueira Filho MA, Rosa JC, de Oliveira Carvalho CR, Seelaender M, Santos RVT Lancha Jr AH. (2010). Chronic low frequency/low volume resistance training reduces pro-inflammatory cytokine protein levels and TLR4 mRNA in rat skeletal muscle. European journal of applied physiology 109, 1095-1102. Zong M, Bruton JD, Grundtman C, Yang H, Li JH, Alexanderson H, Palmblad K, Andersson U, Harris HE Lundberg IE. (2013). TLR4 as receptor for HMGB1 induced muscle dysfunction in myositis. Annals of the rheumatic diseases 72, 1390-1399.

Unfair Dismissal Legislation

Unfair Dismissal Legislation In this paper we will examine the tension between unfair (employee) dismissal legislation and the autonomy of managers to run their departments as they see fit. Interestingly, the question refers to managers right to manage their employees: It should be stated at the outset, unlike the rights afforded to employees by legislation and the common law, which are enforceable rights per se; there is no such right enshrined in the law to protect the autonomy of managers. It is also interesting to note that the question does not ask us to d iscuss the degree to which unfair dismissal legislation takes away managers right to manage their employees effectively or well, or ask us to comment upon whether or not the suppression of managers autonomy is a good or a bad thing for the development of a healthy and effective commercial workplace. We will argue in this essay that such an assessment is central to the question of this paper. After all, for example, the Police and Criminal Evidence Act 1984, which seeks (inter alia) to regulate the conduct of Police Officers, might well be seen to take away rights of the police to arrest citizens, but only does so to protect the citizen from unconstitutional and unacceptable authoritarian practices. Likewise, in the case of unfair dismissal legislation, if the effect is to prevent poor management practice, then this cannot be seen as a negative thing. The worry is that such legislation will interfere with good management, by creating expectations in the minds of employees regarding the standard acceptable processes which govern their employment and as such, might prevent managers from taking the initiative to be creative and progressive in their management approach. The question therefore boils down to whether or not the current unfair dismissal legislation in the UK is sufficiently flexible to allow management creativity to blossom to the advantage of all stakeholders in the employee-management-employer relationship. Unfair dismissal of employees is governed by Part X of the Employment Rights Act 1996, as amended by Part 3 of the Employment Act 2002. The right to not be unfairly dismissed is defined is s94 of the 1996 Act, and s95 of the same act outlines the circumstances which are capable of giving rise to a breach of this employment right. Hepple and Morris (2002) p255 comment upon the amendments to the unfair dismissal legislation introduced by the Employment Act 2002: â€Å"[T]he new statutory standard and modified disciplinary procedures, broad in conception but minimalist in their requirements, ‘are so rudimentary in nature that they afford little protection to employees[and] ‘fall significantly short of the requirements of the current ACAS Code and of the standards of reasonableness developed by tribunals†. This would seem to suggest that this legislation has had little impact upon curtailing the right of managers to manage their employees, especially in light of the fact that there is no significant deterrent effect arising from the remedy contained in s34(6) of the 2002 Act, which only entitles an unfairly dismissed employee to four weeks pay compensation. It also seems apparent that s34(2) of the Employment Act 2002 has reversed the case law decision of Polkey v A. E. Dayton Services [1988] in which it was decided that employers (and, more importantly, their managers) should be reasonable in their choice and use of employee dismissal procedures. S34(2) of the Employment Act 2002 introduced s98A into the Employment Act 1996, subsection 2 of which states: â€Å"[F]ailure by an employer to follow a procedure in relation to the dismissal of an employee shall not be regarded for the purposes of section 98(4)(a) as by itself making the employers action unreasonable if he shows that he would have decided to dismiss the employee if he had followed the procedure.† Again, there is nothing in this section which would suggest that managers rights to employ their own styles of disciplinary procedure have been curtailed: As long as the procedures employed lead to a decision identical to that which would have been generated through adherence to the standard dismissal procedures contained in the UK Employment Acts. It might be argued that that this procedural latitude will not be enforced to its full extent, and therefore that employers and their managers cannot rely upon its provisions to escape liability for nonprocedural conforman ce, but, as Collins (2004) reports: â€Å"The potential width of this exception should not be underestimated†. In regards to this amendment and also to the introduction of the ACAS code under the Employment Act 2002, Smith and Morton (2006) write: â€Å"In spite of government declarations, it is not clear how the ACAS Code and case law can impose a higher procedural standard than the statutory procedures in an unfair dismissal claim, although the test of a reasonable employer (whose action will fall within the range of reasonable responses) remains. Henceforth an employer defending a dismissal may argue that adherence to a procedure above the statutory minimum or the ACAS Code would not have led to a different outcome.† It would therefore seem that, under the new unfair dismissal regime, employers have even more latitude to escape liability for unfair dismissal by procedural unfairness and therefore, even less reason to reign in their managers by insisting on extra training or standard management practices. It should also be noted that under the Employment Tribunals (Constitution and Rules of Procedure) Regulations 2001, the maximum award available to an employer from an employee who unsuccessfully brings a claim in the employment tribunal has been substantially increased as it now, by virtue of the Employment Tribunal Regulations 2004, can also include non-legal preparation costs. This must serve as a deterrent to employees from making frivolous and/or poorly constructed claims for unfair dismissal. Ans so, our analysis of the UK legislative framework on unfair dismissal all point to a conclusion that this regime does not have any significant effect upon the right of managers to manage their employees, so long as the procedures utilized are synonymous by result. However, there is often a big difference between the legal impact of legislation and its cultural effect. Let us now perform a literature review of several key sources in the field of employee management to see if the practical and real effect of the amended unfair dismissal legislation has been to curtail the creativity of managers or otherwise interfere with their right to manage their employees, effectively or otherwise. The first point which can be identified from the literature is that the legislation on unfair dismissal has had different effects on different sized of business. Whilst the research is relatively out of date, it seems clear that the small business sector has been the least affected by the formal dismissal regime. As Harrison et al (1998) write: â€Å"The major studies (e.g. Dickens et al., 1985) are now dated and there have been few attempts to up-date earlier assessments of the impact of unfair dismissal legislation on small firms (e.g. Clifton and Tatton-Brown, 1979; Daniel and Stilgoe, 1978; Evans et al., 1985). This research and the periodic WIRS surveys (Millward et al., 1992) indicated that small businesses were less likely to have formal disciplinary procedures than larger businesses. This would suggest that small business managers autonomy to manage in their own way has not been significantly ‘taken away by the UKs unfair dismissal legislation and its enshrined standar d procedures. This is confirmed by the findings of a case study analysis by Harrison et al (1998) who found that: â€Å"The presence of a formal written disciplinary procedure does not, of itself, ensure that it is applied/observed by all managers, nor that common disciplinary standards will be applied to all employees, or even to all employees in the same occupation, grade, etc. For example, two instances were found where the senior site manager in multi-site companies in the catering sector was not familiar with the requirements of their companies written procedures. Harrison et al (1998) also found, from their interviews, that managers in this sector took a flexible approach to disciplinary action. The problem with this is that the approach is likely to differ from manager to manager with the result that the only way companies can maintain consistency is not to change, remove or replace senior managers: â€Å"[T]here was evidence from many of the interviews of a â€Å"flexible approach† being taken to disciplinary actionThis â€Å"flexibility† plainly has its strengths, but it inevitably also raises issues of perceived consistency or inconsistency among employees of actions taken by different managers [I]ts potential effect on both employee morale and on potential unfair dismissal claims and outcomes, was a principal reason why many organizations have restricted the right to dismiss to senior managers.† Interestingly however, the interviews conducted across multi-site organizations revealed that â€Å"managers were able to draw on the wider resources of their organizations, including the advice and expertise of HR/personnel specialists. In some cases these specialists became involved in helping line managers to handle disciplinary cases, usually with the effect of avoiding major discrepancies.† This would suggest that the UK unfair dismissal legislation has had a noticeable impact upon the rights of managers in larger organizations to manage their employees, the procedures clearly being taken seriously if outside help is being drafted in regularly. In pages 457-458, Harrison et al (1998) discuss the effect of unfair dismissal legislation on ‘management style. They confirm our earlier conclusion that Managers are still acting autonomously despite the unfair dismissal legislation: â€Å"There are acknowledged difficulties in attempting to categorise management styles in organisations, not least because they may vary from one manager to another, and from one situation to another.† McCabe and Rabil (2001) write convincingly on the rights of employees and the impact of these rights on employers and their managers. At page 34 they write: â€Å"‘[T]he most critical right of employees is the right to due process (Velasquez, 1982, p. 327)[D]ue process involves a system of checks and balances, it increases the objectivity of decisions‘the topic of due process in work organizations calls for much greater conceptual development, practical experimentation, and systematic research (Aram and Salipante, Jr., 1981, p. 198). Prima facie, these respective statements seem to conflict with one another: On the one hand, McCabe and Rabil talk of ‘objective decision making, and yet on the other, they talk of the need for ‘practical experimentation. However, I would argue that, rather than being mutually exclusive, these observations demonstrate the ability for fair management autonomy to co-exist with principles of due process, if not necessarily consisten cy. Managers can implement their own style of disciplinary procedures into a workplace as long as these implementations are perceived as subscribing to the princinple of due process and the end effects of these implementations are consistent with the outcomes which would have been reached under the statutory procedures. This confirms what we postulated earlier in this essay; namely, that the unfair dismissal legislation does not significantly impede effective and fair management autonomy, but simply prevents managers from managing their employees in ways which are inappropriate or do not follow the principle of ‘due process. As McCabe and Rabil (2001) write: â€Å"Not all managers know how to manage their work force effectively, nor do they all treat their employees fairly. A good due process system cannot make managers manage more fairly. It may provide a strong incentive for them to do that, but if they don t know how, the process itself will not teach them. In conclusion, I would argue that since the inception of the Employment Act 2002, which amended the unfair dismissal legislation contained in the Employment Rights Act 1996, the UKs legislation on the unfair dismissal of employees is sufficiently flexible to allow employers and their managers the autonomy to create and implement their own employee management procedures, so long as these procedures are capable of yielding fair and equitable decisions. Thus, in response to the specific question, to what degree has the unfair dismissal legislation taken away managers right to manage their employees? I would argue that it has significantly taken away this ‘right. However, in relation to the more important question, to what degree has the unfair dismissal legislation taken away managers right to manage their employees fairly and effectively? I would argue that it has not taken away this right significantly.

Ford Motor Company Essay -- essays research papers

It was once said, â€Å"Those who do not study the past are deemed to repeat it.† On the brink of the new 21st century it is important for us at the Ford Motor Company to take a look at our past to see what has worked and what has not in order to set the standards for the automotive industry. It is also imperative to take a close look at what our competitors have done because we can also learn from their mistakes as well as improve on some of their ideas that have worked for them. It is important to realize that the world is ever changing and therefore what people want, and the market for automobiles is changing as well. Therefore we must first take a look into our competitors, and our pasts before we can then begin to look toward the future of the Ford Motor Company in the 21st century. It was a little over one hundred year ago that Henry Ford first came up with his dream to create an automobile that would change the world. Although it was Henry’s dreams and drive for success that lead him to his achievements it was not without the three giants-steel, oil, and transportation, that were the building blocks for the Ford Motor Company. From the beginning he knew that in order to sell his product and make his company a success he would have to be able to appeal to the masses. At this time Ford was not the only man to be in the small but growing automobile industry. There were others such as David Buick, Ransom Olds, and Billy Durant, who were also trying their luck in this new market. At this time owning an automobile was almost impossible unless one was quite wealthy. Although Buick, Olds, and Durant were all producing autos they were all having trouble selling their products because their production costs were too high. These costs were reflected onto their sel ling price, which was very hard to afford for most of the working class. This is what caused their financial troubles and helped Ford move into the market. He understood that in order to make his company a success he would have to make his automobile one that could be afforded by the masses. While the other producers of autos were more concerned with who had the bigger, better, and faster car, Ford had a different focus. His philosophy was: â€Å"I will build a motor car for the great multitude†¦it will be so low in price that no man†¦will be unable to own one.† It was for the next five years, a young Henry Ford d... ... by the Chrysler Corp. The minivan market is still growing because of the capacity that it offers, its affordability, and efficiency. Although at this time the SUV is the fastest growing market, it is risky to put more effort into it due to the fact that the bigger, faster, gas guzzler craze is probably nothing but a craze, especially as we move into a more environmentally safe future. This has been seen before in the early eighties when this same craze took place right before gas prices jumped and the move to a more efficient automobile took place. American car companies were not ready for this and foreign markets became much more popular. In order not to repeat this history, more emphasis should be placed on the development of a new and efficient minivan that will surpass GM and Chrysler. In conclusion, as we move through the beginning of a new century we must first look to our past to learn what has worked and what has not. After doing so, we can then begin to devise our plans that will move us ahead with the changing times. This can, and will be, accomplished as the Ford Motor Company moves back on top of the automotive industry where it started almost 100 years ago.

Brown v. Board of Education: A Step Towards Equality Essay -- Brown ve

Brown v. Board of Education: A Slow Yet Significant Step Towards Equality On May 17, 1954, in the landmark court case of Brown v. Board of Education, the U.S. Supreme Court unanimously outlawed racial segregation in public schools. The court decision, in light of the continual endeavor of African Americans to ban racial segregation, came hardly surprising. Still, the prohibition of school segregation stirred up hot debates throughout the country and was met with strong opposition, violence, and inertia in the South, where the law mandated school segregation. James Baldwin, an African American writer noted for his ability of weaving narrative and argument and intermixing public and privates experiences, also joined the army of critics. In his essay â€Å"Down at the Cross,† he cites the Supreme Court ruling as an example to help manifest his view that white Americans are reluctant to give sincerely anything to their black counterparts and that concessions made to African Americans are due to Cold War politics. While without doubt Baldwin has more aut hority than most outsiders today in any discussion of the African American experience in the 50s and 60s, he, as a product of this tumultuous era of intense racial hatred, can hardly be considered objective. Indeed, Baldwin is over-cynical in his analysis of Brown v. Board of Education, and his vision of civil rights struggle is too idealistic. A New York Times article published on May 18, 1954, reported in detail the Supreme Court ruling in Brown v. Board of Education and its aftermath. In regards to the High Court’s 9-0 decision, Chief Justice Earl Warren said that racial â€Å"segregation of children in public schools†¦even though physical facilities and other ‘tangible’ factors may be e... ...1995. James Baldwin: Collected Essays. Ed. Toni Morrison. New York: Library of America, 1998. 296-347. â€Å"Dilemma in Dixie.† Time 20 February 1956: 76. â€Å"Editorial Excerpts From the Nation’s Press on Segregation Ruling† New York Times 18 May 1954: 19. â€Å"Historians Laud Court’s Decision† New York Times 18 May 1954: 17. Huston, Luther. â€Å"High Court Bans School Segregation: 9-to-0 Decision Grants Time to Comply.† New York Times 18 May 1954: 1+ â€Å"Ruling Tempers Reaction of South.† New York Times 18 May 1954: 20. â€Å"The Slow March of Integration After 7 Years, 7 Per Cent.† U.S. News & World Report 28 Aug 1961:46. â€Å"What Negroes Want Now.† U.S. News & World Report 28 May 1954: 54-59. Zirkel, Sabrina, and Nancy Cantor. â€Å"50 Years After Brown v. Board of Education: The Promise and Challenge of Multicultural Education.† Journal of Social Issues 60.1 (2004): 1-15.

Characters in Aylin

Aylin Devrimel: She was so far the only tall,skinny,freckled and pony tailed child in her class. She was attending the American Colloge for girls she did not interested in lessons but yet managed to pass her exams with the highest grades. Aylin attended the American College for girls and later went to Paris to continue her education and she began a life with hurried. A hurried marriage which has made her a Libyan princess, a medical education that to pave the way for a successful career as a psychiatrist. And she got a lot of marriages which never lasted long. At the end she was in the American army as a colonel. Leyla Devrimel:She is Aylin’s mother. She always worried about her daughters. She was the pillar of family,clever,talented,strong and beautiful mother. A tumour was discovered in Leyla’s breast and unfortunately she was dying. Leyla died in the autum of 1961. Cemal Devrimel:He is Aylin’s father who worked for the National Rail Company in Ankara. He was very libertine when he engaged with Leyla. After he got married he was very calm and he was a good father. Nilufer Devrimel:She is Aylin’s sister who studied at Barlett school of Architecture and she is seven years older than Aylin. She was to conceive herself to be Aylin’s protector,patron and owner all her life and was to intervene in her life. Aylin was to love her sister all her life. She was really beautiful and she was interested in metaphysical books. As soon as she turned eighteen she got married without to get permission for her parents. Aziz Tansever:He was first husband of Nilufer who the son of a rich businessman. He studied at Economics in England. After the education he had taken a job with NATO in Paris. He was very kind person, helpful and he always love Nilufer. Hilmi Bay?nd?rl?:He is Aylin’s uncle who was childless,he treated Aylin was his own daughter. He had bought luxurious house which Aylin and her uncle lived in Sea of Marmara. Prince Ben Tekkouk:He was first husband of Aylin who prince of Libyan. He was impressed with Aylin and he lived a hotel room with Aylin. He was narrow-minded for her thoughts. He always locked up her in a hotel room and he never want to divorced with Aylin. But they were divorced after a long time†¦ Polat Saran:He was fall in love with Aylin when she got married. He was a student in Paris. Aylin thought that she at last learned the meaning of love with Polat. He was a young man of depth who was interested in literature, philosophy and arts. He was enjoyable and he was two years younger than Aylin. Jean-Pierre:He was second husband of Aylin who was an assistant of physics at University of Lausanne and he instructs Aylin. He was very long man like a bean stalk, clever, civilizen, well-educed and also he was a physic genius. Betin: Aylin’s neighbor and she became her bosom friend. She was two years younger than aylin. Betin knew her friend so well that she was sure. Kas?m Gulek:He was second and last husband of Nilufer. He was as old as Nilufer’s grandfather who has been a bachelor for years. He was a politician whose house was in Ankara-Bahcelievler. Paswak:He was fall in love with Aylin who has got dark skin, curly hair, green eyes and he was tall. He was the UN Ambassador to Afghanistan and he was very attractive man. He was married and he has got three childrens. Misel Radomisli:He was third husband of Aylin who was a psychologist from Turkey. Misel and Aylin introduced them yo their friend whose name was Zeynep. He knew all the songs and he played piano with his husky voice. He was mature person but he left Aylin. Zeynep:She was Aylin’s friend who was a doctor of psychiatry with a brilliant future, she was talented, tall, blond and witty and she looked more like an American than a Turk. She was Aylin’s housemate. Tayibe Gulek:She was a Nilufer’s daughter who lived with Aylin and Misel for eduction. She was as close to her aunt as she could never be to her mother. Nuri:He was manservant in Aylin’s house. Laurie Kraus:She was Aylin’s patient who has attempted suicide twelve times. She was very young and angry. Josep Cates:He was fourth and last husband of Aylin. He had a daughter who was a problematic addescent. The girl was Aylin’s patient. He was a film producer and a bit too fat. Also he was adore of Aylin. Sister Nancy:She was Scottish. She was Aylin’s first patient who was a member of the Church and she wasn’t talkative and shy person.

The Shack, a Discussion of Symbolism

2/16/09 The Shack: A Discussion of Symbolism The Shack, written by William P. Young, tackles one man’s quest for faith and reassurance in God through several metaphors, parables and symbols. These symbols are used to compare the story religion itself; and from this comparison it is easier to grasp a deeper understanding. However, with this underlying symbolism, it’s possible to over analyze and disregard the fictitious nature of the book. Despite this, there are many symbols within The Shack that are essential to the story and the deeper significance within it. Symbols are used within The Shack to really enunciate the relationship transition that Mack experiences while visiting the shack and the new found relationship that he develops within the Trinity. Symbolism within The Shack is found almost everywhere, with symbolism it is possible to understand God through the analogies expressed. These analogies range from simple to complex and have many dimensions; the symbol itself and the reality it exposes. There are many different symbols hidden within the shack, some are obvious and some are vaguer. One of the more obvious pieces of symbolism would be the story of the Indian Princess that Mack tells Missy. (Young, 30-31) The story is a clear representation of the death of Jesus Christ. Missy is unnerved by the death of the Indian Princess and Jesus and raises the essential question, as to why God is so mean? (31) Mack answers the question the best he can but it still unnerves him. He says that Jesus didn't have to die, he chose to. He then tells Missy that  God will never ask us to do something like that, as Jesus already covered it. He's shaken though by the depth of his young daughter’s question. However, not quite as shaken as he will be in the days ahead as he wonders the same thing himself. In the coming days ahead When Missy is abducted, Mack will think back to this, thus, creating distrust in God for Mack. Now that Mack has developed a type of disbelieve in God, he becomes immersed in another piece of symbolism that he has taken to calling â€Å"the Great Sadness†. †¦he [Mack] allowed himself to consider the range of horrendous possibilities, and once it started he couldn't stop; the imaginations of good and evil all mixed up together in a soundless but terrifying parade. 53) This â€Å"Great Sadness† seems to be a lot like depression but there are some things here that seem to even go beyond such a simple definition. It appears to more than physical, more than psychological; it's almost a spiritual type of thing that hits to the very core of his being to where his entire world is impacted by its presence. It haunts his dreams, and leaves him in a stat e of almost perpetual fatigue and anguish. It can be argued that this state was brought on solely because of his daughter’s disappearance; however that may just be one of the factors contributing to the â€Å"Great Sadness†. Mack’s â€Å"Great Sadness† seems to come more from his loss of faith because of the loss of his daughters which could imply that both of these are the causes of his grief induced state. Whether it’s depression, or something else, Mack has a condition in which pain becomes so overwhelming that there are few options other than suppressing the pain, which is what Mack chooses to do. One of the contributing sources to Mack’s great sadness is the loss of his daughter, Missy. Missy can also be viewed as yet another symbol within The Shack. She is innocent and unassuming; therefore she can be regarded as somewhat of an inner child or symbol of youthful innocence. And now Mack could clearly see the voice that had called his Missy. It was Jesus playing in the middle of his children. (168) However, with her disappearance she brings despair and sadness to her family, therefore she is also representative of great pain and loss. Missy, can also be compared to Jesus. She was innocent, but ended up dying for no reason. Although her death was tragic and hurt her family, Mack manages to gain a new relationship with God from it. Much like Jesus, who died unjustly, but ended up saving humanity, Missy in a way saves her father. Another symbol found several times throughout the story would be the lady bug. Before the family leaves to go on a camping trip, Missy asks her mother and her father if she can bring her insects with her. Her father says yes, while her mother says no, because they will be safer at home. This is symbolic because it turns out that Missy would have been safer at home too. Perhaps the most noted symbols in the entire story would be the physical human representations of the Trinity. God is represented by a large African American woman; however this is just the form that God chose to spoke to Mack through, because â€Å"Papa† (God) says that God is neither male nor female. (93) Jesus is portrayed as a clumsy Jewish man. While the Holy Spirit is an Asian woman, who behaves rather strangely and flits in and out of Mack’s vision and can appear in more than one place at once, (128) these are all metaphorical representations of the manifestation of the Trinity. Mack in his first meeting with God following his cathartic regeneration of unloading his anger and rage sees God in a quite different manner than he expected, which is why God is portrayed this specific way. This materialization of God in this form is important because this isn’t a literal assembly with God. This is a parable or metaphor that represents Mack’s introduction to a God that isn't the remote, presentiment, ominous, hypercritical figure that Mack has believed him to be, until now. To reveal myself to you as a very large, white grandfather figure with flowing beard, like Gandalf, would simply reinforce your religious stereotypes, and this weekend is not about reinforcing your religious stereotypes. (93) God or Papa in The Shack isn’t revealing himself in all of his splendor and sanctity for a specific reason. This is because the general rationale of this weekend in the shack is focused upon constructing a relationship with God. Through this, Mack discovers the idea that God's love extends so much that God has chosen to reveal himself in a manner that Mack can relate to and identify with. God also wishes for Mack’s religious stereotypes to be abolished, so he can be closer with God. Mack’s religious stereotype of God in his head is similar to Gandalf from Lord of the Rings, like a sort of grandfatherly figure with a long white flowing beard. (73) So, Mack is shaken immensely when God appears to him in the way that he does, in order to try to bring himself down to Mack’s level. Through the symbolism in this story dealing with the trinity, Mack begins to start the road to restoration nd healing. The whole meeting in the shack is symbolic in itself because it is possible that it did not even occur in reality. Mack discovers that his accident was on Friday night, and also when he wakes up wakes up in the shack and it is cold (237) and also he appears to be in the same spot on the floor where he fell asleep (79) near the old blood stain. This leads to the conclusion that the manifestation of the trinity, may have occurred just not as a part of reality, more as in a visionary meeting. These events are seemingly real as Mack experiences them and he is able to grasp that there is a truth being represented here through this weekend at the shack and from that he reaches the truth about his relationship with God. Even though it is possible to conclude that the actual meeting did not occur, there is a reality here in the truth of the concepts and life changes that occur because of this meeting. The purpose of this metaphorical vision was to save Mack, so he could forgive and mend his relationship with God. Parables, symbols and metaphors are all essential elements in The Shack. They help to intertwine the pieces of the story together and allow for greater significance. Although some of the symbolism is blatant and quite obvious; there are other pieces of symbolism that are vaguer and harder to pick out. The Shack is a story about, healing and forgiveness, and within the tale of anguish and spiritual redemption there are symbols that act as signposts helping to lead Mack to conclusion and build a stronger relationship with the Trinity. Works Cited Young, William P. The Shack. Newbury Park, CA, 2007

Diabetes Type 1: Stem Cell Research

Stem cell therapy involves the direct transplant of islet cells to potential areas in the pancreas that have the ability to store and facilitate the differentiation of beta cells in the body. Such treatment is currently under progressive study in terms of its effectiveness and the possibility of fortifying the islet transplant’s resistance to autoimmune attacks antibodies. We discuss the actual procedures and different alternatives of stem cell therapy for DMT1 patients. The discussion covers the potential problems being confronted by such treatment, such as stem cell scarcity, autoimmune attacks against the islet transplants, etc.Lastly, discussion also covers the potential alternatives of the treatment, specifically (1) human embryonic stem cells, (2) cultured stem cells and (3) potential xenogeneic resources. In the conclusion, we have found several problems currently being faced by stem cell therapy. These problems include the scarcity of available islet grafts or transpla nts and the autoimmune risks that can dramatically hinder to the success of the therapy. However, various studies are currently being explored in order to obtain potential alternatives, such as xenogeneic stem cell resources, embryonic or progenitor alternatives, etc.Furthermore, we discover different methodologies in stem cell culturing and preparation techniques that confront the immunity problems most especially in post-transplant phase. These include the usage of different immuno-suppressing drugs, such as gastrin, etc. 2. Introduction 1. 1 . Type 1 Diabetes DMT1 is essentially the absence or severe insufficiency of insulin due to the autoimmune (e. g. CD4 interleukin attacks, cellular necrosis, macrophagial reactions, etc. ), environmental or viral destruction of beta cells (e. g. iral infections from mumps, etc. ) or insulin-secreting cells in the pancreas. Although, autoimmune reasons are the most commonly associated etiology that cause DMT1 condition. Apparently, the body an tibodies, specifically interleukins and minor interferons, recognize the antigenicity present on pancreatic islets as foreign substances, which consequently triggers autoimmune responses. The prevalence of DMT1 in United States is approximately 1 in 2500 for the age group of 5 years old, which 1 in 300 for every 20 years of age group.Although the most considerable nature of DMT1 is its autoimmune nature, prevalence of DMT1 in United States and European nations largely depends on two causations: (1) genetics and (2) lifestyle. According to the EURODIAB collaborative study, a registry involving 44 countries in Europe, states an annually increasing rate of DMT1 with approximately 3 to 4%, with a larger increase in some central and eastern European countries . The prevalence of DMT1 among 191 World Health Organization (WHO) member states and for all age groups worldwide is estimated to be 2. % in 2000 and 4. 4% in 2030 . DMT1’s beta cell destruction does not only consider the neg ative effects towards insulin production. Deficiency in insulin can directly lead to moderate to severe hyperglycemia that can further trigger problems, especially in (1) neural systems, (2) peripheral and central vascular regions, (3) cardiac and (4) kidney areas. Vascular complications among DMT1 are associated to different cellular dysfunctions, such as Endothelial Progenitor Cells (EPC) that induce metabolic stress and vascular angiogenicity especially when the cells are decreased.The primary principle that explains the metabolic and cardiovascular dangers of this illness is the increased of tonicity in the blood or also known as fluid hypertonicity. Due to the increased surge of blood glucose levels, fluids, such as blood, lymph, interstitial fluid, etc. , become thicker than its normal viscosity. With this fluid condition, the circulation exerts tremendous vascular and hyperosmolar pressure from major vessels to minor arterioles and veinuoles. Eventually, the prolonged pressur e can lead to various complications, such as eye retinopathy, nephronic damage, nerve ending necrosis, etc.The common treatment being prescribed among DMT1 patients is the continuous administration of insulin injectables in order to fill in the body’s insulin requirements. This is done to temporarily replace or fill in the insulin insufficiency of the body. However, insulin therapy and maintenance are lifetime measures that require continuous commitment, which can greatly interfere in the person’s self-esteem and lifestyle progression. To resolve these potential emotional and psychosocial damages of the temporary insulin therapy, permanent treatments, such as stem cell implants, autoimmune suppressors, etc. are currently being studied with hopes of permanently curing the disease. Stem cell studies have carefully focused in determining the potential strategies in order to induce beta cell differentiation and cellular regeneration, especially among those damaged or destr oyed islet cells. Clearly, with cellular differentiation and regeneration s the goal of stem cell treatment, vast numbers of research discussed in the latter part of the studies have intensively focused their explorations in the disease’s autoimmune nature.Modern studies of beta cells have always been associated to the macrophagial and lymphocytic activities of T-cell mediated antibodies, such as CD4+CD25+, CD+ T-cells, etc. Most studies are determined in configuring the possible strategies of resolving, preventing and/or countering the DMT1’s autoimmune response on both original islets and implant islet grafts. In animal trials, most commonly rodents, autoimmune elements of the disease are somehow resisted when significant dosage of immune-inhibiting drugs (e. g. nfliximab, daclizumab and sirolimus, etc. ) are applied on the islet implants prior to the commencement of stem cell implantation.Several studies (e. g. Gastrin applicationetc. ) have found promising strategi es that can immunize the transplant grafts and possibly the original islets themselves from the autoimmune destruction rendered by the disease; although, modern science has not yet considered the safe applicability and effectiveness among human trials due to the conflicts encountered by the studies, such variations of drug responses or autoimmune actions. On the other hand, the signs and symptoms of DMT1 and DMT2 are both related to the two principal components of diabetes: (1) hyperglycemia and (2) hypoinsulinemia.DMT1 commonly presents its condition with the classic manifestations of polydipsia, polyphagia and polyuria . Physiologically, the three principal signs of DMT1 are extremely integrated and fostered by the body’s sympathetic natural response. For example, due to the hyperglycemic state of the body, the satiety centers of the brain triggers polydipsia in order for the body to increase its fluid intake aiming to dilute the tonicity or increased blood glucose levels. In the process, the body increases the fluid contents in the blood increasing as well the kidney workload in processing urinary output; therefore, producing polyuria.Consequently, fluid loss also causes significant electrolyte losses and glucose malabsorption that trigger body weakness. In order to compensate, the body triggers polyphagia that aims to increase food consumption. The three latter manifestations are considered the cardinal or principal manifestations of DMT1 common to all patients. Weight loss, fatigue, blurred vision, pruritis and muscle wastage are the secondary symptoms that follow with the continuous manifestations of DMT1 cardinal signs .The secondary complications of DMT1 can further aggravate if the physiological hyperglycemia and other associated signs and symptoms are not resolved. Tertiary complications involve severe manifestations that can be fatal in nature, such as diabetic ketoacidosis and possibly diabetic coma. 1. 2. Causes of DMT1 DMT1 has three poten tial origins that are currently under extensive study, namely (1) chronic autoimmune destruction of beta cells, (2) environmental destruction of beta cells that is commonly viral in nature, and (3) genetic abnormality in beta cells and/or insulin receptors .The autoimmune etiology of DMT1, as discussed earlier, involves the activity of interleukin-1 protein cytokine that principally triggers the immunologic response of CD4+ T cells against beta cells. The autoimmune nature has proven the relationship between beta cell destruction and islets’ inflammation due to interleukin invasion; however, studies have not yet determined the principal source of this cytokine production . The issues surrounding the autoimmune proposition in the DMT1 condition is the communicating element/s induced by the disease that activates antibodies’ response against the islet cells.As of the recent studies, no specific communicating agent has been discovered linking both DMT1 condition and its a utoimmune reaction towards islet cells; although, there are numerous evidences that reveal the exact autoimmune attacks against pancreatic islet cells, most significantly on the beta cells. Meanwhile, viral causations have also been associated to the occurrence of DMT1. Common viruses, such as mumps, rubella and coxsackie, have been associated to the destruction of beta cells, which eventually triggers the chronic drop of insulin production .Cytokine-interferon alpha (IFN-alpha) has been associated with the occurrence of DMT1 with hypothetical viral origin. According to clinical reports, IFN-alpha is brought by environmental viruses (enteroviruses) that trigger immune-mediated beta cell destruction. Significantly, therapeutic agents targeting IFN-a may potentially be beneficial in the prevention of type 1 diabetes and autoimmunity . Lastly, genetic abnormalities min beta cell progenitors and cellular differentiations are also becoming part of the controversial cause of DMT1.The idea of genetic causation of DMT1 involves the reduced activity of embryonic progenitors in pancreatic endothelial, which consequently lessens the cellular differentiation of beta cells. With small beta cell count in the body, insulin production becomes insufficient causing cellular tension for insulin production. Prolonged state of hypoinsulinemia or complete absence of insulin in the blood usually results to DMT1 complications. Islet transplantation or stem cell therapy considers the destroyed islet areas that need replacement.According to Rother and Harlan, if patients with greater body mass indices and/or with insulin resistance were also considered for an islet transplant, the 3,000 transplantable islet preparations presently achievable would likely be sufficient to restore euglycemia to fewer than 1,000 patients per year, or less than 0. 1% of patients with T1DM, or approximately 0. 005% of those with either form of diabetes. Despite of the technological advancements of stem cells and islet transplants, most parts of DMT1 condition and autoimmune functionalities are still left undetermined.The scarcity of islet stem cells is not the only problems being faced by islet transplant therapy but also the impending variations of autoimmune activities of the body. Controlled experiments have been conducted on both rodents and primates; however, the results most of the time vary when applied to human samples. Although, such islet therapy have already been applied to human sample and proven to cause independent insulin production; although, medical issues, such as alternative stem cell or islet graft sources, risk of anaphylactic rejections, etc, are still being studies extensively.Therefore, scarcity and further study of the procedure are necessary to further the application of islet stem cell therapy among DMT1 patients. 1. 3. Therapy for DMT1 Stem cell transplant of islets of langerhans, specifically the ß -cells, is now considered as alternative treatment in tr eating Diabetes Mellitus Type 1 (DMT1); although, not all DMT1 patients are applicable candidates of stem cell therapy. Antigenicity testing and severity of DMT1 manifestations as well as autoimmune response to the treatment are usually evaluated before considering stem cell transplant.Through the process of genetic engineering, the autoimmune response of DMT1 towards the islet cells can now be countered by replacing the cellular necrosis of ß-cells. The study explores the different sections of ß–cells stem cell transplant, particularly on (1) the actual procedure, (2) allogeneic and xenogeneic possibilities, (3) the actual condition of DMT1 and (4) the pathophysiological principles involved in the process of disease progress and stem cell therapy.The case of DMT1 is autoimmune by nature wherein the body acts negatively to the islet cells by recognizing these cells as a form of foreign objects. Theoretically, the body’s macrophages and interleukins are alarmed by the foreign or abnormal structuring of islet antigens, which probably resulted due to the extensive response of the cells thriving within high insulin-needing environment. In response, the body’s immunologic centers trigger macrophagial and anti-body mediators (e. g. GAD65 Ab – Glutamic Acid Decarboxylase Antibodies, Iinsulinoma Antigen 2, etc. attacking and destroying the body’s own pancreatic tissues . During these conditions, islet cells chronically declines in number as macrophagial actions subdue and destroy both progenitor cells in the pancreas and those differentiated islet cells, which include the beta cells. With the destruction of progenitor cells, the rate of cellular differentiations for further beta cells and other islet cell types (e. g. alpha cells, etc. ) decline leaving the body deficient of these endocrine hormones.Furthermore, as the existing and pre-existing beta cells die due to autoimmune damages, the capacity of the islet cells to regener ate also decline, which eventually decreases the number of existing beta cells within the islets. Theoretically, According to Xu, Wang and Hou (2008), as the body’s insulin requirement heightens and prolonged, the remaining beta cells experience physiological stress in insulin production, which, if not prevented, can lead to a negative feedback mechanism wherein insulin production complete shuts off its production.DMT1 patients experience decreased and/or absence of insulin production, and usually peaks between early adolescence (10 to 14 years of age) to middle adulthood (30 and above) . Pancreas manifests lymphocytic infiltration and destruction of islets of langerhans, which consequently causes depletion of insulin production. During the past few decades, studies on islet transplantation through mesenchymal stem cells (MSC) have shown to improve the metabolic conditions of DMT1 patients. However, the performances and study results using MSC remains to be questionable.Trans -differentiation of MSCs into insulin-producing cells (IPCs) is considered the principal concept of the therapy; however, other reports have negated these results claiming that it is too difficult to assume and determine the timing and extent of improvement by only analyzing the effects through trans-differentiation. Cellular differentiation and self renewal can greatly vary depending on various conditions, such as existing drug therapies, immunologic sensitivity, duration of the illness, other existing disorder including complications dealt by DMT1, etc.Similar to other beta-stimulating treatments, MSC is considered growth factor stimulant of the surrounding beta cells, which aids in the mechanism of self duplication rather than cellular proliferation. According to Xu, Wang and Hou (2008), â€Å"MSCs transplantation into diabetic animals may prevent apoptosis of injured pancreatic beta cells and enhance regeneration of endogenous progenitor cells through paracrine actions† ( e. g. angiogenic, cytoprotective, anti-inflammatory, mitogenic and anti-apoptotic effects, etc. ). MSC studies are still on the process of development along with animal trials.MSC therapy alternative is process for treating principally the occurrence of hyperglycemia in DMT1; however, the process remains an assumption and currently being studied. In the study of Ezquer, Ezquer and Parrau (2008), MSC procedure has been detected to also contribute to tissue regeneration (e. g. bones, cartilage, infracted heart, brain and kidney). In the study, a test subject with streptozotocin (STZ)-induced type 1 diabetes (C57BL/6 mice) has shown significant cellular neogenesis on pancreatic and renal function as well structure.Somehow, MSC has triggered a potential role of becoming a promising alternative as pancreatic progenitor cells that possess the capacity to initiate cellular differentiations. After the subject received a 0. 5 x 10(6) MSCs via ex vivo expansion, the sample has shown significa nt reduction in blood glucose levels and euglycemic values after a month. With MSC acting as the islet’s alternative progenitor cells, beta cell differentiation can progress to the development of other beta cells, which if continued can trigger cellular regeneration among produced existing beta cells.According to final conclusions of Ezquer, Ezquer and Parrau (2008), â€Å"MSC administration resulted in beta-pancreatic islets regeneration and prevented renal damage in diabetic animals. † This evidence shows the possibility of using MSC in initiating both cellular differentiation and self-duplication. Altthough, Xu, Wang and Hou (2008) still consider this process as an experimental alternative therapy for DMT1 condition. However, the study sample did not consider the potential effects of human autoimmune responses against these MSC grafts.Autoimmune responses can risk the success of graft transplant considering the increased antigenicity present among these islet transp lants, which is a considerable issue that arises in the results of their study. Meanwhile in the study of Feng, De-quan and Yan-hua (2008), they have focused on MSCs derived from human umbilical cord blood (UCB) in order to facilitate cellular transdifferentiation into beta cell alternatives via in vitro. In the study, UCB samples are obtained, while presenting MSCs are isolated for analysis via flow cytometer.In the process, islet-cellular differentiation has been induced for 15 days with or without extracellular matrix gel. This extracellular matrix gel provides an enriched environment that nourishes cellular requirements aiding in their differentiation and consequent self-duplication. With the help of chemiluminescent immunoassay system (CIS) in detecting glucose activity and insulin response, the studied found out that insulin positive cells (25. 2 ±3. 4%; UCB n=42) within ECM gel have produced functional islet proteins after 9 days of pancreatic differentiation.Considering th e feasible environment setup by ECM, the possibility of creating a zone wherein autoimmune reactions are considered nullified has also become one of the propositions that theoretically explained the results of the study. According to the conclusion of their study, MSC can actually differentiate into islet like cells in vitro and ECM gel. Fortunately, with the advent of modern technology and introduction of somatic stem cell transplant, the depletion of ß–cells can now be replaced with new generating ß–cells through stem cell implantation.In 1990, Scharp et al. has brought reports of success in the process of transplanting islet cells to patients with DMT1 through the process of improved islet isolation techniques (developed by Ricordi, Lacy and Finke et al. 1988) . Isolation techniques aim in discovering alternative progenitor sources of progenitor cells that possess the capacity to differentiate into insulin-producing cells that can serve as essential alternativ e for beta cells.Aside from pancreatic progenitor cells, the study has also discovered potential sources in the kidney, liver, bone marrow and other vital organs of the body. Isolation techniques usually require individualized culturing of islet transplants prior to the actual therapy. With the introduction of ß–cells implantation, different forms of islet transplant (e. g. billiary installation of islet cells, xenogeneic sources of islets, etc. ) have been considered throughout the process of stem cell therapy. On the other hand, certain reaction problems produced during the process (e. . anaphylactic response, incompatible cellular transplant, insulin-sensory impairment, etc. ) have also been observed in throughout the process of therapy. Despite of the potential therapeutic permanence of islet transplant therapy against DMT1 condition, most medical specialists (Kabelitz, Geissler and Soria, 2008; Xu, Wang and Hou, 2008) consider this treatment as last resort therapy for severe cases of DMT1. Stem cell therapy is not yet considered as a general treatment applicable for all sorts of DMT1 conditions.According to Kabelitz, Geissler and Soria (2008), the concepts in the cellular treatment of DMT1 are (1) the replacement of islet cells by islet-like cells derived from embryonic or adult stem cells, and (2) promotion and establishment of immunological tolerance of islet cells towards self-antigens through regulatory T cells and/or tolerance-promoting monocyte-derived cells. Studies have explored possible ways in dealing with the confronting problems of the procedures, such as scarcity, autoimmune sensitivity, etc.In the preceding sections of the discussion, the two concepts are further explained considering the possibility of merging the two procedures in order to attain maximum efficiency in the DMT1 cellular therapy. 3. Modern Techniques in Treatments of DMT1 1. 1 Islet Cell Transplant The principal concept of stem cell therapy is the harvesting of pot ential and/or adult health cells that are transferred to failing or degenerating organs. As for DMT1 conditions, islet transplantation, specifically on ß–cells implantation, is the most impressive treatment that shows promising permanent cure for islets’ autoimmune degradation.According to Hussain and Theise, â€Å"stem-cell therapy here implies the replacement of diseased or lost cells from progeny of pluripotent or multipotent cells. † According to Haller, Viener and Wasserfall et al (2008), UCB-derived MSCs are significant autologous progenitor inducers that can initiate cellular self duplication or regeneration. In their study using 12 autologous UCB infusions, preliminary results show significant slowing of endogenous loss of beta cell degradation among DMT1 children subjects.Aside from the slowing of hyperglycemic actions induced by DMT1, Keymeulen (2008) has proposed the possibility of actually blocking or preventing the autoimmune destruction of beta cells in DMT1 conditions. In the study, Keymeulen (2008) proposes the short-term humanized anti-T-cell antibody treatment that aim to inhibit the t-cell activities and preserve the residual beta-cells for at least 18 months in order to induce cellular regeneration and stabilize metabolic control of the body over the rising glucose levels.By applying Anti-Thymocyte-Globulin, tacrolimus and mycophenolate mofetil to a non-uremic C peptide negative DMT1 patient, marked decrease in autoimmune activities has risen to more than 80%. Another principle of stem cell transplant in islet cell therapy is biologic differentiation wherein a pool of undifferentiated precursors (e. g. Human Islet-derived Precursor Cells or hIPCs, etc. in pancreas appears to be a series of stem cell that further differentiate to islet-endocrine cellular population: (1) Glucagon-producing alpha-cells, (2) insulin-producing beta-cells, (3) somatostatin-producer in Delta cell, (4) pancreatic polypeptide secreting cells . Both of these cellular somas act as the cellular surrogate of ß–cells that shall replace the depleted or damaged cellular source in the pancreas . Cellular differentiation holds the key in inducing growth to the depleted beta cells in the islet of langerhans.According to the study of Abdi, Fiorina and Adra (2008), islet transplantation (ppluripotent stromal cells) provides great potential for diversifying the cellular lineage even with postnatal damaged tissues. The study of of Abdi, Fiorina and Adra (2008) support the idea of cellular renewal and differentiation giving more emphasis on the mesodermal origin. In such case, the study introduces the concept similar to other studies (e. g. immuno suppression of T-cell activity, increasing beta cell antigenitcity resistance, etc. wherein the introduction of MSCs or islet transplant pluripotent cells may induce an immunomodulatory effect, which eventually facilitates cellular regeneration. The study of Seissler and Schott (20 08) also supports the idea of cellular differentiation and self-renewal; however, they have questioned the capacity of supporting the cellular capabilities of stem cells derived from adult pancreas or non-pancreas. During cellular differentiation of endocrine tissue, precursor cells secrete multiple hormones prior to final maturation of differentiated cells that secret single classification of hormone.Most of these hormones are actual growth hormones that enhance cellular differentiations and regeneration. Although these actions are most of the time slow-phased and are very much vulnerable to immunologic attacks, some studies (e. g. Piper, Brickwood and Turnpenny, 2004; Lai, Schneider and Kidszun, 2005) suggest that once islet cells have regained its stable cellular disposition, which can varies depending on the prevailing physiological atmosphere (e. g. decreased immune activity, prolonged hypoinsulinemia, etc. , the cellular proliferation and restorative scheme can pursue more rap idly than its common phasing. In the process of islet transplant, beta cells are produced as part of the general cellular differentiation produced by broad cellular differentiations . According to Rosenburg, Lipsett and Yoon et al (2004), once islet cell quantity have increased to a stable position and the environment requires extensive insulin production, autoimmune response of the body against these cells are seen to decline dramatically.Once islets have differentiated from progenitor populations, the cells migrate towards the surrounding exocrine tissues. With the help of angiogenesis resulted by vascularization of islet’s arteriolar blood flow, specific cells present in the islet progenitors, beta cell progenitor, increase its differentiation phase, which consequently increases the number of beta cells present in the pancreas . As beta cells increase, the body’s glucose-perception also enhances considering the increased quantity of glucose sensing beta cells.The di fferentiated beta cells react against the decreased body insulin levels by producing insulin, which further stimulate beta cell’s massive proliferation in islets of langerhans . Upon stimulation of cellular differentiation under insulin deficient environment, islet transplant may significantly continue with its differentiation and regeneration schemes without the heightened danger of autoimmune attacks. This theoretical physiology can serve as the actual basis for considering the value of restoring stable beta cell count within the body.However, the conflict that needs resolution is the safety of islet grafts upon its initial stage of transplant. Differentiation of beta cells is the primary target of islet stem cell therapy among DMT1 patients. These cells are highly specialized cell type, phylogenetically developed, and regulators of glucose homeostasis in higher forms of organisms. However, some studies suggest (Montanya, 2004; Vinik, Rosenberg and Pittinger, 2004; Hermann, Margreiter and Hengster, 2007) the inverse relationship present between cellular proliferation and differentiation of islet implanted stem cells.The most common problem that arises during post-transplant phase is the decreased differentiation of beta cells, which, in some cases, are not enough to fill in the body’s insulin requirements . However, Dor, Brown and Martinez (2004) assert that Beta cells, during post-stem cell therapy, do not base the production of additional beta cells in the rate of differentiation; rather, beta-cells proliferate through the process of self-duplication .This is considered as an argument in the idea proposed in the latter section wherein it proposes the nullity in achieving cellular stability in both differentiation and regeneration once specific rate of beta cells are reached in the process. Although the proposed theory does not entirely in-distant with the latter, the argument suggests that beta cell proliferation solely derives from the pre-e xisting beta cells obtained via transplant, which further proliferates via the process of cellular regeneration and not entirely differentiation.As for the critique, cellular differentiation is regarded as of little importance due to its low contribution in cellular proliferation. According to Dor, Brown and Martinez (2004), â€Å"Our analysis shows that pre-existing beta-cells, rather than pluripotent stem cells, are the major source of new beta-cells during adult life and after pancreatectomy in mice†¦ These results suggest that terminally differentiated beta-cells retain a significant proliferative capacity in vivo and cast doubt on the idea that adult stem cells have a significant role in beta-cell replenishment. Xunrong, Hua and Soo (2005) support the argument through their study indicating the process of autoimmune blockage (Transforming Growth Factor-TGF-[beta]1) rather than the concept of cellular differentiation brought by stem-cell therapy . In the study, they have m ention the capacity of growth factors, such as TGF, to provide temporary autoimmune suppression that blocks the hazardous effects of this bodily responses.With increased angiogenesis or vascularization, the newly introduced cells (beta cells) can rapidly and freely proliferate as long as adequate oxygenation from rapid blood supply is present, and autoimmune suppression is being facilitated by the growth factors. According to Xunrong, Hua and Soo (2005), â€Å"Syngeneic islet grafts failed by day 17 in all untreated mice, whereas Ad-hTGF- [beta]1 therapy prolonged survival of islet grafts. Our data demonstrate that systemic TGF-[beta]1 gene therapy blocks islet destructive autoimmunity, facilitates islet regeneration, and cures diabetes in diabetic NOD mice†.TGF-[beta]1 possesses the functions of temporarily blocking the autoimmune response against the transplanted islet graft as well as triggering cellular regeneration channeled through self-duplication. Considering the argu ments propose by the two latter studies, this study still concludes the essential contributions of cellular differentiations brought by pre-existing progenitor cells from stem transplant or original sources; since, these component holds the appropriate physiological distribution of islet cell re-categorization and reproduction. 1. 2 Stem Cell TransplantationContrary to the concept of cellular differentiation and proliferation, post-stem cell transplant on islet cell is said to induce aggressive self-renewal due to the presence of significant growth components (e. g. TGF-[beta] 1, hemo-erythropoetin,etc. ) that enhance pre-existing beta cell proliferation and protect the cells from autoimmune attacks. Through the use of a DNA analog-based lineage-tracing technique , the study has found that precursor cells do not actually contribute to further differentiation of adult beta cells, and not even during acute beta cell regeneration.Rather, beta cells are being produced through self-renew al or duplication wherein a programmed cell division occurs through a refractory period preventing excessive or massive beta cell proliferation. Although, as argued by various studies (Lee, Grossman and Chong, 2008; Gershengorn, Anandwardhan and Wei, 2004), theoretically, differentiation rate usually surges during the initial phase of cellular implantation; however, once the cellular count of these differentiated cells stabilize, self-renewal or cellular regeneration of the existing beta or islet differentiated cells follow.Thus, explaining the inverse relationship between beta-cell proliferation and differentiation. Current studies in both allogeneic and xenogeneic stem cell sources are now being studied with marked emphasis on autoimmunity reversal or even autoimmunity tolerance. According to Lee, Grossman and Chong (2008), â€Å"stem cells from hematopoietic sources, such as bone marrow and fetal cord blood, pancreas, intestine, liver, and spleen, promise either new sources of i slets or may function as stimulators of islet regeneration†.Through stem cell introduction of pancreatic cells, specifically islets of langerhans, the adult human beta cells pre-existing in the stem cell transplant exhibit hormonal expression . Contrary to the concept of cellular proliferation, stem cell transplant essentially increases beta-cell resistance to autoimmune destruction of DMT1, which consequently facilitates the proliferation of beta cell in the islets of langerhans.According to various studies (Linning and Madkuhar, 2004; Strobel, Yuval and Stirman, et al. 006), aggressive beta cell self-duplication is the actual cause of beta cell proliferation whether by implantation of TGF-[beta] 1- induced islet cells or the traditional islet replacement. Implanted islet progenitors, when cultured, expresses 1% of endocrine cell proliferation during the first 48 hours up to 6% after five days . According to Rosenberg, Lipset and Yoon (2004), increasing the mass of beta cells after the event of post-immune destruction induces a 175-amino acid pancreatic acinar cell protein called, Islet Neogenesis-Associated Protein (INGAP) peptide, which acts as a stimulator of beta cell mass stimulator.INGAP peptide, similar to TGF-Beta growth factor, triggers cellular neogenesis enabling the rapid rate of cellular regeneration after significant results from cellular differentiation. The production of INGAP protein is commonly cited during post-phase of islet transplant. However, according to Lai, Irina and Eugen et al. (2008), gene modification present in cell transplantation process is problem considering the extensive cellular processes involved in the adaptation and transplant reception.Although, applications of several viral vectors (e. g. adenovirus-associated vectors, etc. have proven to be successful, but hESC is considered a more potent alternative due to its feasibility for genetic manipulation and self-renewal. During the mass replication of beta cells, the small portion of the cells stops in the process of neogenesis, while other beta cells are reserved for continuous replication at a very slow phase. After this scenario, the counter-attack of autoimmunity is usually expected; hence, treatment regimen that suppresses immunologic reaction on islet grafts are usually being instilled to the transplant sample prior to the therapy.This procedure increases the resistance of the graft cells against the autoimmune reactions triggered by the body. With a disorder such as DMT1, the chances of beta cell recovery become lesser due to the persistent autoimmune destruction of beta cells . The decreased capacity cellular replication in the adult beta cell is very much limited to result in a significant regeneration rate following autoimmune damages . Likewise, chronically increased metabolic requirements, such as increased insulin demand, can cause beta cells’ incapacity to fully cope in the given physiologic environment.This gives the appro priate rationale for implanting islet cells in the area of depleting beta cell in order for the progenitors to differentiate and proliferate mass beta cells in the area. According to the study of Urban, Kiss and Kovacs et al. (2008), hematopoetin centers of the body, such as bone marrow, may harbor cells that can actually influence the self-duplication of beta cells. Such concept is greatly associated to the principle of angiogenesis implying the value of appropriate oxygenation in the area of developing cellular clusters.In the study, sex-mismatched bone marrow cells (BMCs) and syngeneic or allogeneic MSCs are administered to a mice sample with streptozotocin induced DMT1, and consequently led to the rapid tissue regeneration after a single injection of a mixture of 10(6) BMCs per 10(5) MSCs. Other agents that can forcefully differentiate beta cells during post-islet transplant are INGAP (Rosenberg, Lipset and Yoon et al. , 2004; Weir, Toschi and Inanda et al. , 2004), GLP-1 and GL P-1 receptor agonist exendin-4 (Li et al. , 2004), betacellulin and activin A (Brubaker and Drucker, 2004), and the combination of EGF and Gastrin (Rooman and Bouwens, 2004) .These agents can actually force the cellular differentiation providing immediate and ensured processing new beta cells with much more lessened risks of being attacked by immunologic elements. Betacellulin, Activin A and Gastrin are the common immuno-suppressants being applied to most controlled studies on islet transplants today due to its availability and decreased result variations; although, some studies still explore the applicability and effectiveness of these agents in the process of triggering cellular differentiation.Meanwhile, Melleoul (2006) suggests that cellular differentiation of beta cell during post-islet transplant is controlled by series of genetic activators and transcription factors . Its absence in mice and humans during embryogenic to postnatal development may actually lead to pancreatic ag enesis. After such condition, cellular differentiation becomes restricted principally to ß cells wherein cellular regulation of genetic expression in ß cell-specific genes occurs.Furthermore, such condition facilitates the mediation of the glucose effect on insulin gene transcription, which shows that any exposure of ß cells to high glucose even with short period of time can actually stimulates insulin gene expression. However, chronic exposure to high glucose levels can actually trigger negative effects, such as alteration in ß-cell functions and gene transcription. PDX-1 transcription breaks down upon exposure to chronic hyperglycemia, while stimulation of beta activity is seen during acute hyperglycemia.Such genetic modifications can actually enhance the survivability of islet transplants within a new host considering the autoimmune function being rendered by continuous DMT1-induced CD4 immunoglobulins. According to Phillips and Tang (2008), using cellular, molecular and gene manipulation strategies, each islet transplant can actually be guarded or attain enhanced resistance even with the hostile environment directing immune rejection, inflammation, hypoxia and apoptosis.Genetic engineering provides cellular modification for constructing gene sequences. Considering the conflict existing in mass beta cell replication and autoimmune destruction, high quantities of beta cell replication during post-islet transplant has been associated to the reduced impact of autoimmune damage. With the help of CTL antagonists in terms of restricting T-cell activity, the regenerative capacity and neogenesis of ß-cells are expected to progress through forced-differentiation therapies.Initial activities between autoaggressive Cytotoxic T-lymphocytes (CTL) and beta cells are terminal event leading to cellular agenesis of ß-cell, which consequently affects both progenitor beta cells and those potential self-replicating beta cells from the pool of potential ß-c ell replenishment . Progression of CTL is unlikely to be stopped; hence, the only appropriate idea of treating the pathogenesis of DMT1 is the replenishment of beta cells that have been damaged throughout the ongoing autoimmune attacks.According to Dor (2006), progenitor cells present in the pancreas, specifically on pancreatic ducts, acini, islets of Langerhans, and other parts of the body (e. g. bone marrow, spleen, etc. ) are even more potent source of beta differentiation . However, these progenitor cells provide variable cellular differentiation rate that can compromise the process of stem cell therapy especially if the non-ideal progenitor cell source are used in the procedure.To compensate, most studies have explored the possibility of using embryonic-obtained stem cells that contain the most feasible progenitor cells aside from the ideal pancreatic progenitors. Although beta cells are differentiated from progenitor cells during embryonic phase of pancreatic development, the progenitors (marked by expression of neurogenin 3 and the paired box protein Pax-4) are seen to disappear upon birth . Such disappearance actually implicates a significant process that are undergoing with beta cells, which actually trigger fundamental change in their mode of maintenance and expansion.The cellular process begins from the embryonic progenitor-cell-based differentiation and further progress to massive self-regeneration. In the study of Nagaoka, Fukuda and Hashizume (2008), betacellulin (BTC) is analyzed as another potential growth factor that can induce progenitor-cell-based differentiation and cellular self-duplication. BTC possesses ErbB receptor tyrosine kinases that induces differentiation and cellular mitosis, especially among acinar-derived AR42J cells, transforming these cells into insulin-producing or beta functioning cells. As supported by Parnaud, Bosco and Berney et al. 2008), BTC-induced purified beta cells within allogeneic islet transplant graft enhanced by ECM have yielded a population of 91. 4 ±2. 8%. Nagaoka, Fukuda and Hashizume (2008) mention that BTC â€Å"independently and preferentially binds to two type I tyrosine kinase receptors, the EGF receptor (ErbB1) and ErbB4†. Significantly, BTC induced graft transplants are seen to contain mutant protein that promotes the rapid differentiation of pancreatic acinar AR42J cells to insulin-producing cells, which is actually the opposite with AR42J cells that contain wild-type BTC protein.Rapid differentiation is not entirely beneficial in nature as this can cause hyperplasia. According to Min Cho, Lim and Yoo et al. (2008), BTC, together with Nicotinamide sustained PDX1 expressions, actually induced cellular differentiation C-peptide proteins; although, insulin mRNA is found to be very low. 4. New Advances in Stem Cell Research The theory between stem cell differentiations versus beta cell progenitor self-duplication still coincide the need to restore pre-existing beta cell p ool from the ongoing damage made by the autoimmune CTL.Stem cell is still an important consideration in replenishing these depleted resources. However, due to the extensive problem on stem cell donors and sources, stem cell therapy is not yet considered part of an ideal DMT1 treatment. According to Korsgren, Lundgren and Felldin (2008), new alternatives for stem cell therapy are currently being explored with aims of determining other contributing components that induce cellular graft survivability and reduction of immunoresponse against DMT1 mediated antibodies.During the process of transplantation, the isolated islets transplant grafts are induced to embolise the liver after its introduction via the hepatic portal vein, which is a procedure that is unique in the area of stem cell implantation. However, such procedure is only an example of low efficacy procedure. A novel view on the engraftment of intraportally transplanted islets is presented that could explain the low efficacy of the procedure. As supported by Rother and Harlan (2004), and Hardikar (2004), only 750 patients have already been treated using allogeneic islet transplants since 1974 despite of the billions of DMT1 cases worldwide.Various alternatives have been proposed in order to counter such scarcity, specifically: (1) embryogenic blastocyst and post-natal resources, (2) culturing of stem cells, and (3) stem cell grafting using xenogeneic resource (e. g. umbilical cord, etc). The isolation of human embryonic stem (hES) cells has been introduced as a potential prospect for filling in the scarcity of beta cells, specifically through islet transplantation . Embryonic stem cells are harvested from blastocysts, while adult stem cells are from postnatal organisms.The process involves (1) the culturing and plating of embryoid bodies in insulin-transferrin-selenium-fibronectin medium, (2) supplementation and maintenance using N2, B27, and basic fibroblast growth factor (bFGF), (3) lowering of glucose c oncentration to reduce the physiological pressure on premature beta cell, (4) bFGF is withdrawn to prevent excessive growth stimulation, and (5) nicotinamide addition . Counteracting transcription-polymerase chain reaction found out an enhanced cellular expression of pancreatic genetic chains within the site of cellular differentiated cells.Using the Immunofluorescence and in situ hybridization analysis, the findings have revealed a significantly increased percentile range of insulin-expressing cells within the cellular clusters. According to the study of Xia, Ayala and Thiede et al. (2008), hESCs, with the help of drug-inducing transgene expression (in vitro and in vivo) forms >95% purity level, which significantly implies the high possibility of regulating genetic expression of hESCs. After the islet transplantation, genetic expression of the cells remained stable and regulated with the help of an orally administered drug.Although, according to Chung and Stainer (2008), cellular o rigins that regulate pancreatic B cell induction and genetic expression is not yet fully understood. Differentiation of embryonic stem (ES) cells to islet phenotype, identification and utilization of pancreatic precursor/stem cell from adult sources, and the cultivation of new islets from adult stem cells obtained from various tissue types or directly form other terminally differentiated cell types are the common areas being covered by islet transplant or stem cell research for DMT1 immunogenetics research .In such case, cultured embryogenic or adult somatic islet cells are transferred from its original placement to appropriate locations in the body of a DMT1 patient. Human Embryonic Stem Cell (HESCs) or ES possesses the capacity to continuously differentiate to cells that express both endoderm and pancreatic progenitor function, such as Foxa2, Sox17, Pdx1, and some islet endocrine hormones (e. g. beta cells) . According to Kroon, Martinson and Kadoya et al (2008), cellular therapy for DMT1 requires the renewal of human beta cells and not entirely the replacement of the degraded ones.In order to induce regeneration, pancreatic endoderm must be stimulated through the use cellular mediated glucose-responsive endocrine cells present within hESCs. The hESC-derived insulin-producing islet-like clusters (ILCs) comprises of 2 to 8% of human C-peptide-positive cells, glucagon-positive and somatostatin-positive cells. The study has detected a content of 70 ng of insulin/mug of DNA being produced through these hESC-derived ILCs, which is statistically higher than the innate fetal islets.In addition, cellular differentiation of hESCs induces the formation of Embryoid Bodies (EBs) that stimulate the gene expressions of POU5F1, nestin, FOXA2, ONECUT1, NEUROD1, PAX6, and insulin as long as the glucose environment is within 25mM levels . In the essence, implantation of hESCs in autoimmune-damaged islets can mobilize the islet cell differentiation through genetically expresse d progenitors from the islet transplant medium. Furthermore, continuous genetic expression is expected since the body’s glucose levels also influence the cellular differentiation of beta cells.Stem cells derived from hESCs places markers of development for endoderm, pancreatic and ß-cell development, glucose sensing, and production of mature insulin . Meanwhile, most studies have also centered in protein-based cellular communication involved during cellular differentiation phase after stem cell implants have been introduced. According to Kroon, Martinson and Kadoya (2008), therapeutic tests using a mice sample with 3000 transplanted human islet cells indicate that hESC derived pancreatic endoderm can actually aid in antibody resistance.In the study’s conclusion, they have pointed the definitive evidence proving the capacity of hESCs in generating glucose-responsive and insulin secreting implanted cells. Interestingly, in the study of Yu, Vodyanik and Smuga-Otto et a l (200), hESCs are found to be programmed by specific four genes, OCT4, SOX2, NANOG, and LIN28, which actually determines the pluripotent capacity of the embryonic stem cells and the characteristic of cellular differentiation. Although, the study concludes that the genetic mapping and processes involved within these newly discovered hESC genes are still in the process of intensive studies.Implanted stem cells actually integrate their needed functions for initiating the mechanism of glucose responsive regulation present as pre-proinsulin mRNA and expression of insulin C-peptide in vitro (Clark, Yochem and Axelman, 2007). Following transplantation into mice, cells become insulin and C-peptide immunoreactive and produce plasma C-peptide in response to glucose. The results of the study suggest that embryonic germ cell derivatives (e. g. ILCs, etc. ) may eventually function as a potent insulin producing cells .The use of islet-derived or stem cell therapy using embryonic cells remain exp erimental due to the challenges of cellular differentiation. Currently, the problems being faced by the treatment is the availability of stem cells that can possess the appropriate capacity to induce cellular differentiation and regeneration. According to the mentioned studies, simple cellular implantation is not entirely enough due to the greater risks imposed by the body’s physiological reaction against islet grafts.Hence, another issue arises in determining the best anti-immunity function or tolerance enhancer of islet graft transplants; although, latter studies have already discovered potential enhancers that can disregard or at least lessen the impact of cellular degradation brought by DMT1 immunity. Lastly, new advances of genetic modification techniques that shall increase cellular differentiation and renewal rates are already in the process of development. 5. Discussion In the research of Froud, Ricordi and Baidal, islet stem cells are cultured under steroid-free immu nosuppression and are transplanted to 16 DMT1 samples.The cultured islet stem cells have undergone a period of in vitro culture-process with heightened necrosis resistance through TNF- a (Tumor Necrosis Factor) blockade that aim to improve islet engraftment and provide alternative to fresh human islet transportation. The results of the study suggest that the implantation of cultured human islet allografts cause a reproducible insulin independence in all subjects under the series immunosuppressant infusions (a. intial Infliximab infusion, b. daclizumab and c. irolimus maintenance), comparable to that of freshly transplanted islets (Edmonton protocol) .In the absence of supplemental infusions (nfliximab, daclizumab and sirolimus), the results of the study have incurred 11/14 (79%) subjects that produced insulin independence at 1 year, while other 6/14 (43%) samples have gained this capacity after 18 months. Surprisingly, the same test subjects have maintained their insulin independenc e until 33  ± 6 month span. Furthermore, the findings have observed that patients are able to maintain their graft function while under the immunosuppressing infusions.According to the results, 8 out of 14 patients have suffered chronic partial graft losses that are likely immunological in nature considering that 5 of these already received supplemental infusions. Currently, 11 out of 14 subjects are in the receiving immunosuppressing infusions, and 8 (73%) of these are already manifesting insulin independence. The study significantly demonstrates the possibility of withholding the immunologic response upon exposure to certain immunosuppressant (e. g. nfliximab, daclizumab and sirolimus, etc. ).Although, the study has not mentioned the possible side effects and complications that such infusion can provide towards the body as a whole. However, since the stem cells are the only ones infused with these immunosuppressants, the chances of systemic immunosuppression are less likely as l ong as the dosage infused with the stem cells remain appropriate and feasible to the body’s normal function. In another culture study brought by Pinzon, Lakey and Brand (2005), they have used the combination of epidermal growth factor (EFG) and gastrin in order to induce beta cell neogenesis specifically on pancreatic exocrine duct cells .These growth factors also carry the risk of triggering extensive cellular neoplasia over-cellular multiplication; although, studies have already found drug induced techniques that can contain the cellular differentiation and regeneration upon introduction within the body system. In the study, human islet cells are placed under four weeks culture study in a serum-free medium with EGF (0. 3  µg/ml) as the control variable and gastrin content of 1. 0  µg/ml.Beta cells have shown significant increase in cultures with the combined medium of EGF and gastrin (+118%), while +81% for cultures with EGF alone. The EGF-gastrin culture has been obser ved again for the next four weeks, but without the said combination. Impressive results have shown beta cells progressive increase in quantity for the culture previously infused with both EGF and gastrin (+232%). Comparing these results from the latter discussed studies, EGF and gastrin have actually trigger cellular differentiation and self-duplication due to their growth factor properties.In the study of Suarez-Pinzon and Rabinovitch (2008), gastrin growth factor combined with epidermal growth factor (EGF) can actually restore pancreatic islet beta-cell mass and even reverse hyperglycemia even in the absence of immunotherapy in mice samples with artificially induced-DMT1. Reversal of hyperglycemia is most likely due to the increase in insulin production that counters the effects of DMS1. With the appropriate amounts of insulin secretion in the blood, the glucose tonicity will consequently be absorbed by the cells granted that the diabetic anomaly does not consider the insulin rece ptor functionalities within cellular surfaces.In the study, EGF dose of 10 microg/kg and gastrin dose of 30 microg/kg via intraperitoneally have been administered to 10 sample DMT1 mice. In terms of glucose levels, the samples have shown a marked decline from blood glucose of 23 +/- 2 mmol/L to 12 mmol/L within 36 days of individual EGF administration, while 19 days in individual gastrin administration. When combined, the decline in the samples’ glucose levels is already present within 11 days.In addition, the cellular islet counts have increased from 13. 0 +/- 0. x 10(5) cells to 29 +/- 2 x 10(5)cells, and considering the marked decrease of surrounding CD45+ leukocytes have also been observed. Therefore, such combination (EGF plus Gastrin) is confirmed to reduce blood glucose levels, prevent autoimmune activity of DMT1 mediated CD4 cells and increase cellular differentiation. Lastly, aside from hESC’s and cultured islet transplants, another potential source of stem ce lls currently being studied is from animals, known as xenogeneic sources . Pig islets are considered the best option available for xenogeneic transplants.According to Rother and Harlan (2004), such potential alternative are now being studied for different considered potentials, such as: Pig islets have been considered as potential source of islet stem cells aside from human source (a) The fact that humans had been treated with pig insulin for more than 60 years (b) Favorable husbandry — in that the species has large litters with offspring that attain adult size rapidly and with relatively robust islet numbers (c) The fact that pig islets respond to glucose in the same physiological glucose range as human islets (d) Existence of suitable societal-cultural relationship between the speciesDespite of the potential capacity of pig islets in acting as alternative stem cell resource, studies (Hering, Wijkstrom and Graham et al. , 2006; Rood, Buhler and Bottino, 2006) have identified its increased immuno-response towards CTL and autoimmune attacks initiated by DMT1 disease. Autoimmune attacks are the principal conflict considered in the process of islet transplantation wherein even if the graft has been successfully implanted, the risk of failure in the procedure is still considered possible considering the effects of autoimmunity triggered by increased antigenicity in the graft transplant.In one study, acute rejection caused the death of two macaque samples through cellular rejection mediated by CD4+ and CD*+ T cells and macrophages . In order to increase the effectiveness of xenografts after post-transplant phase, different culture infusions have been studied to prolong the life of pig islets xenografts. CD4 antibodies are usually being activated upon detecting significant system foreign antigens, which are usually introduced by bacteria, virus or any material that enters the body systems.In this principle, researchers (Kirchhof, Shibata and Wikkstrom et al. 004) have pointed their assumptions in the possible presence of antigens within xenotransplanted islet grafts. In addition, cellular infusions are considered to be at great risk due to the potential intrusion of incompatible antigens that might induce transplant rejection, and eventually autoimmune degradation of transplanted islet cells in the body. This condition is currently under extensive analysis and consideration since even with successful islet transplant, autoimmune response due to heightened cellular antigenicity can still pose the failure of the stem cell therapy.Due to this genetic dilemma, some studies (Kirchhof, Shibata and Wikkstrom et al. 2004; Komoda, S. Miyagawa and T. Omori et al. , 2004) have focused in determining the potential drug enhancers that can improve transplant antigenicity, especially among xenogeneic sources. First, with the infusion of islets from N-acetylglucosaminyltransferase-III (GnT-III) transgenic pigs, pig islet’s xenoantigenicity have significantly declined prolonging the survival of islets for the next five days of culture study. In another study, pig islets subjected for xenotransplantation are tested with alginate encapsulation.The transplant to tested in a primate, specifically a monkey-Cynomolgus maccacus . Adult pig islets encapsulated in alginate under optimal conditions (n=7) or not (n=5) are transplanted under the kidney capsule of the non-diabetic primate sample. Meanwhile, additional samples have received empty capsules (n=1) and non-encapsulated pig islets (n=2) as controls . The results of the study show the rapid inviability of non-encapsulated and encapsulated islets with no alginate and not in optimal condition.Implanted pig islets under optimum alginate encapsulation showing significant prolonged islet survival for as long as six months. However, despite of the experimental success, the study still regards the conflicts encountered by the processes (e. g. variations of graft antigenicity, etc). 6 . Conclusion DMT1 is a condition manifested by increased and frequent manifestations of hyperglycemia caused by the insufficient production or depleted insulin levels. The most universally recognized cause of beta cell destruction is the autoimmune etiology caused by CD4 interleukins, and other associate antibodies.The aims of the therapy are the induction of cellular differentiation while facilitating as well the renewal of the existing and pre-existing beta cells in the islet graft transplant or in the remaining original islets. However, the principal conflict of the procedure is the interference caused by the autoimmune reaction of the body towards the transplanted islet grafts; although, recent studies have continuously explored different possibilities of suppressing autoimmune responses and forcing cellular activities.Stem cell therapy is a potential prospect for permanently treating the condition of DMT1 considering the main concept involved in its pathogenesis – destru ction of beta cell or insulin producing cells. The processes, physiology and pathological considerations in the stem cell therapy of islet transplant involve the criticality of autoimmune response towards the islet transplant.The controversy of such treatment is the effectiveness of implanting whether the islet cells containing stem cells based on the concept of cellular differentiation or islet cells with pre-existing beta cells based on the concept of cellular self-renewal. Despite of the argument between the two perspectives involve, another main issue arises, specifically the scarcity of stem cell from allogeneic donors. According to the approximated statistics, only 750 cased of DMT1 have successfully obtained the stem cell transplant of islet cells considering the billions of other DMT1 patients existing.In order to resolve such scarcity, various forms of stem cell resources have been proposed and are currently under extensive studies, specifically (1) human embryonic stem cel ls, (2) cultured islet stem cells, and (3) xenogeneic sources specifically the pig islet stem cells. According to most studies, autoimmune damage progress if cell count of beta cells is introduced insufficiently to the recipient body; although, stem cell therapy is nearing towards its potential of being a significant cure as beta cell replacement and insulin producer.