Paleoneurology and the evolution of mind

What is â€Å" intelligence † ? What is â€Å" biologically programmed behaviour † ? How make these behavioral forms associate to other facets of the biological science of the animate beings that possess them, and to their generative biological science in peculiar? How does intelligence associate to learned behaviour and more specifically, to human civilization? â€Å" Biologically programmed behaviour ‘ explains most, but non all, non-mammal craniate behaviour. Early surveies of non-mammal craniates characterized behavior as â€Å" replete † -a term that suggested that such behaviours are fixed and changeless. Later surveies documented both a grade of flexibleness and the ability to larn new behavioural forms by non-mammal craniates. Such surveies have besides shown that mammals, in general, have a greater repertory of erudite behaviours than earlier craniates. â€Å" Biologically programmed behavior † is, hence, better understood as a scope of programmed behaviours which have increased unusually with the development of the mammal biological composite. The neurological footing for learned behaviour and intelligence are, in big portion, due to alterations in the generative system. Internal fertilisation foremost occurred in the development of reptilians. In the development of placental mammals, there was non merely internal fertilisation, but besides embryological development in utereo. Such a generative system provides a footing for the animate being to turn into a developed province before holding to confront the external universe. Placentation, a female parent ‘s ability to provide foods and O to a developing embryo, is non without disadvantages ; in animate beings such as the higher Primatess, the female parent ‘s blood watercourse and the developing embryo blood watercourse have a close connexion with the placenta. In many placental mammals, there is a instead non-porous membrane, which separates the maternal blood stream from the embryologic blood stream, while leting foods to go through. If there is major mutant i n the embryo, which is reflected in the embryologic blood watercourse, the female parent ‘s blood stream will non interact with the mutant and will non bring forth antibodies, which would kill the embryo. In the higher Primatess, this membrane is much more permeable and much more efficient in the transmittal of foods. A disadvantage is that any major embryologic mutant, which is reflected in the embryologic blood stream, will bring forth antibodies against the mutant ; this usually consequences in self-generated abortion or abortion. Uterine development has helped mammals insure the greater success of their progeny. The mammalian endurance scheme is known as the â€Å" K scheme, † and it is based upon a high parental investing in specie endurance. Fostering a smaller figure of offspring ensures a higher per centum of those offspring will make generative adulthood. A decrease in birth figure is associated with birth of unrecorded immature in most mammals. This scheme is different from the craniate â€Å" R scheme, † where the parent produces a big figure of eggs, which when fertilized produce a big figure of immature. The difference in these two endurance schemes can be supported by the different attitudes toward decease. In worlds ( and other mammals ) decease of immature mammals is a serious injury ; in vertebrates the decease of a hatchling is the regulation of nature, and endurance is the exclusion. The stimulation -response cringle characterizes much of the behaviour of earlier craniates. A centripetal input comes into the craniate encephalon, which is linked to a stereotype motor end product. A celebrated illustration of â€Å" biologically programmed behaviour † is the generative behaviour of the three-spined Stickleback of the Rhine/North Sea. An external event triggers a series of biologically linked behaviours, which consequences in successful reproduction. As spring occurs in North Sea, there is more daylight. This stimulates the pineal secretory organ of the female, which, in bend, signals the hypothalamus, which produces a neurotransmitting chemical to the pituitary secretory organ. This in bend consequences in the secernment of pituitary endocrines, which stimulates the ovaries to bring forth 1000s of eggs. This gives the female a swollen belly and is a â€Å" mark stimulation † to the male prickleback. In response, the male does a â€Å" zigzag dance, à ¢â‚¬  which is referred to as a â€Å" fixed action form. † The dance, in bend, acts as a mark stimulation to the female, who follows the male to the nest, and through an extra series of gestural stimulations and fixed action forms, moves through the nest to lodge the eggs. The male so passes over the eggs with sperm. Natural choice favours the keeping of these neurological tracts in the males and females because they successfully function to bring forth fertilisation ; to set it the other manner, if a female has a neurological alteration where she would non acknowledge the zigzag dance, she will non be able to reproduce. In a series of experiments, Tinbergen and his pupils were able to demo that the conceited abdomen of the female prickleback is the originating mark stimulation. Raising male prickleback in entire isolation, they introduced them into the H2O with both populating females every bit good as with metal lineations of females with conceited abdomens. Regardless ( and even when the lineation of the female was grossly distorted ) , the males produced the zigzag dance. It was â€Å" hardwired † in their nature. Individual animate beings, hence, have small direct input in altering behavioural sequences. Once the female has laid her eggs, and they have been fertilized, that represents the terminal of parental investing. It is non difficult to see how clime or other alteration can quickly stop an full species that relies on biologically programmed behaviour for reproduction. The absence of daytime for a individual spring in the North Sea would intend the terminal of prickleback reproduction. Young mammals are born incapacitated and dependent, and they go through a drawn-out babyhood and young person of fostering wholly dependent on grownup coevals. Because the parental investing of mammals is the attention of really little figure of offspring, the duty falls chiefly on females. There was besides an development of mammary secretory organs for this postal nurturing period. During this clip of weakness, the animate being has the freedom to detect the universe, while being feed and protected. This generative system of mammals, hence, allows the mammal intellectual cerebral mantle to integrate and internalise the sensory patterns the animate being has experienced. The animate being is utilizing intelligence -the â€Å" ability to build a perceptual theoretical account of the universe inside your caput † ( Jerison ) . The mammal encephalon has developed into a construction, which provided the footing for both learned behaviour and intelligence. The function of the encephalon is to enforce a theoretical account of the universe on centripetal informations, and supply appropriate responses to it. This is non an wholly new development ; it represents an development of the intellectual cerebral mantle as a go-between between perceptual experience and response ( motor end product ) , and the integrating of input from an acute auditory sensory system. Learned behaviour and intelligence are non the same. Learned behaviour is the ability of an animate being to screen through a assortment of possible behavioural results, and choice which behaviour is appropriate. When driving a auto, for illustration, an person has to pick when it is appropriate to turn right at a ruddy visible radiation. Learned behaviour is portion of the mammal form, but it is differentially distributed ; worlds have an tremendous ability for erudite behaviour, compared to the limited degrees of other mammals. The cardinal account is the intellectual cerebral mantle. Choice behaviour is located in the frontal lobe. Worlds have the greatest ability to detect, compose, and internalise many complicated theoretical accounts of the encompassing universe. Intelligence and learned behaviour are necessary for worlds to keep a societal world over the long-run. In the words of Ward Goodenough, â€Å" civilization is the criterions of behaviour learned and understood by members of a society. Not all members of the society learn the same set or scope of criterions, and this distinguishes the rank is a assorted sub-groups of the society. † The ability of mammal immature, during socialisation, to larn the behaviours appropriate for endurance in their environment and in cooperation within societal groups, is basically the ability to obtain civilization. This ability distinguishes these mammals from the â€Å" difficult wired † biologically programmed behaviour of non-mammals. There are many mammals that are lone ( i.e. a cat ) , and they do hold learned behaviours, which they obtained during the dependence period. Social mammals, nevertheless, have the exact criterions of erudite behaviours. Culture is, hence, the composite that allows worlds to keep societal world over the long-run. This is non specific to worlds, nevertheless, because all societal mammals trade with the issues of communal life. During babyhood, the kid observes the universe around him/her and internalizes the behaviours of grownups. Children in societal groups so play together, because drama is the pattern of grownup behaviours. Human civilization, in the words of Ralph Holloway, is defined as the â€Å" infliction of arbitrary signifier on the environment. † Rock tools, for illustration, are iconic, because they are of arbitrary form. The mental ability to enforce this form on the environment is a consequence of the development of the intellectual cerebral mantle. Such neurological alterations would non hold been possible without alterations in the mammalian reproductive system.Mentions:Goodenough, Ward H. â€Å" Culture. † Blackboard. Web.Holloway, Ralph L. â€Å" Human palaeontological grounds relevant to linguistic communication behaviour. † Blackboard. Web.Jerison, Henry J. â€Å" Paleoneurology and the Evolution of Mind. † Blackboard. Web.Mann, Alan. â€Å" The Brain, Power Point Presentations 1 and 2. † Lecture.

Distribution of Product: Daing Na Bangus Essay

I.Products Boneless Bangus Boneless Bangus also known as â€Å"Daing na bangus† was one of the famous foods in the Philippines and it is one of the delicious and nutritious foods loved by most Filipinos. Fish like bangus contains proteins, fats, vitamins, calcium and iodine that is needed by our body towards a good and a healthy lifestyle. Through the process of deboning milkfish and marinating with vinegar and garlic, the product Daing na bangus became known in the country. Dagupan City is one of the famous sources of daing na bangus particularly Bonuan for its perfect and delicious taste. Daing can be served with plain rice or fried rice for breakfast, lunch, and dinner. They are readily marinated to a good taste that will surely be loved by the customers. Boneless bangus lasts for about ten (10) days up to two (2) weeks upon good preservation. If not, it will be perished. Daing are placed into packs that consist of three (3) medium pieces. The group gets the product by pack; usually the price from Dagupan is ranging from P75.00 to P80.00 per pack. The group sells them at P100 per pack so as to earn a reasonable profit. Source of the Product The product daing came from Magsaysay Market Avenue, Fernandez St. Dagupan City Pangasinan. It is quite far from Muà ±oz, Nueva Ecija that is why the transportation cost may lessen the profit that the group can be earned. Luckily one of the group member’s brother works there. During weekends he goes back to Muà ±oz to spend time with his family. The group asked him if he is willing to be the medium for delivery, so that the group can save a minimal amount of transportation cost. Fortunately he agreed upon the request of the group. From Dagupan market, daing na bangus is being transported in Muà ±oz, Nueva Ecija then the group distributes it to their customers. II. Why Product was chosen for Distribution? The group thinks of a food product that will be easily bought by the customers at an affordable price with nutrients good for our body. The group chose daing for distribution activity because the product is easy to market since it is affordable and considered as an all time-favorite by most Filipinos. It can be served in the breakfast, lunch, and even dinner time. The group also considers the source of the product; one of the group members has already a contact to the dealer of daing in Dagupan City that will surely deliver fresh daing at the time the customers needed the product. Selling perishable products takes difficulty for the distributors because they need to ensure that their products are still in good condition when it is delivered to final consumers. Perishable products need time, proper management, and proper handling upon selling to be able to guaranty customers that they will receive a good product. The group also wants to ensure that the consumers will be able to receiv e proper nutrients. III.Persons involved Tasks of the Group Members All group members performed equal tasks. The products are equally distributed to the group members and they are able to sold daing to their respective places, neighbors, friends, classmates and schoolmates. Other group members sold it directly in the market, canteens and stores. After experiencing selling individually, the group agreed to sell it as a whole. Starlet, being one who is responsible to contact her brother have done her part by informing him when and how many daing orders are going to be delivered to the group. She is also responsible for bringing the products to the group after she gets it from her brother. Maila have done her tasks successfully in distributing and selling daing. On the first order, Maila, being one of the members of the JBEES organization, asked help to the organization in distributing and selling bangus, they successfully sold out eighty (80) packs of daing na bangus. After that, she sells bangus by herself to gain profit as well as experience selling such product. She sold it to her family, neighbors, friends, and even professors in CLSU. Shekinah, another member of the group, have done her part successfully by selling daing not only to her family, neighbors, friends, and schoolmates but also to her churchmates and to stores near to their house. Jay-Ann sold her daing to her friends, classmates and boardmates. By means of connecting to other people, called networking, the group had fast distribution and sale. While selling daing, she also sold mushrooms on her own in order to have a high profit. Starlet uses her connections to other people in order to sell her products immediately; she sold bangus to her organization, family and friends. Chris John Paul also used his being a marketer. After he sold proportionate number of daing, he makes Maja Blanca on his own strategy and sold it to his classmates. After selling individually, the group agreed to help each other for faster distribution and sale. The group sells inside CLSU that is why it takes short period of time selling those products. The group went to Old Market and offered them the product. They also offered daing to the tricycle drivers inside CLSU and to the construction workers currently working in the hostel. About twenty workers bought the product and they really liked its taste that is why they bought another twenty pieces to the group. The group makes sure that their product, daing na bangus, are fresh and delicious. Before placing an order, the group has to make sure that they can dispose the product fast to maintain its good taste. If there are excess daing, the group puts it on a proper storage to maintain the good quality of the product. Reasons Why Tasks are done As part of the distribution activity the group members has to cooperate to the group. Each member did those tasks because they want to acquire more knowledge about selling products. They have to experience persuading customers to buy their products. They want to have a good communication to other people to easily sell and distribute their products. They did those tasks to be more trained and confident on dealing with different people in the near future. Also, they want to have profit from the selling activity. And most of all, they want to see themselves done those tasks successfully and confidently. IV. How Undertaken Duration of the Activity The selling activity started on June 28, 2010 and ended on August 23, 2010. V. Who were the customers and why were they chosen? The group members’ customers are their classmates, friends, professors, family, neighbors, nato tricycle drivers, and construction workers in CLSU. The group sold daing to their classmates since many of them are living on a dormitory, and boarding house. Their classmates commonly had problem thinking of their viand for their meals that is why some of them bought daing from the group. Since one pack of daing consists of three (3) pieces, they can share it to their board mates or roommates so that the cost will be cheaper. They also sold daing to their friends inside and outside CLSU. They spread the message about the product through the use of cellphone. If for some reasons their friends have no money, they will still find ways to endorse the product to their friends so that it will be more fast and easy for the group. The group, being persistent to their selling activity, sold their products even to their professors. Mostly, their professors are easy to persuade since most of them have their own family and they always think of a dish for their family’s dinner before they got home during afternoon. That is why they are easy to convince and they are familiar to the boneless bangus’ deliciously taste. During the first distribution, some of the group members bought daing for their family’s consumption. For them, it is really worth buying because of its taste and nutrients. Commonly, it can be served with a mixed tomato, onion and â€Å"alamang† or other vegetable dishes. It can also be served on breakfast with fried rice which commonly favored by most family members. Neighbors are easily reached by the members, most of them often stayed at their house that is why anytime, they could get the products. The nato tricycle drivers are quite hard to persuade into buying the groups product, daing, their main reason is their low daily income. The group exerted patience on persuading them until such time there are drivers who bought the product. The construction workers are currently working on CLSU hostel, upon convincing them they first thought of their salary because they usually get their salaries during Saturdays and we sell daing on weekdays. On that case, a deal has been made. The group sold daing to them on credit. The group could give the Boneless bangus to them upon delivery from Dagupan and so they are going to pay on the stipulated date. VI,. Approach to Customers Convincing people to buy â€Å"Boneless Bangus† is quite difficult for the group. Aside from the fact that the product is in good quality, delicious and affordable; a good approach to customers is highly important. First, the group introduced themselves as a marketing student and selling is part of the distribution activity as a fulfillment to their subject Marketing305. Second, they approached their customers politely and educate them about the product; where it is made and how it is being made. Their selling skills helped them easily dispose the products. They make sure that they are knowledgeable about the product they are offering, and have a good customer relationship to their buyers. These are the elements to have a successful selling activity. Benefits and Advantages of the Product Nowadays many people die from cancer, heart attack, high blood pressure, high cholesterol, diabetes, and other diseases because of their bad eating habits. That is why one must have to be conscious about their health. The product â€Å"Boneless Bangus† is nutritious that is rich in proteins, fats, vitamins, calcium and iodine. Nutrition experts say that protein from fish like bangus contains more of the essential amino acids needed to build and repair cells for the body. Aside from protein and iodine, fish also gives fat which is a source of heat and energy for work and play. Fat from fish is easy to digest because it has a low melting point. Calcium is also found in fish and this helps in body-building and regulating processes and is distributed evenly in the body. Vitamins B2 and B5, called niacin and riboflavin, respectively, are also contained in fish. These B-vitamins help keep the eyes and skin particularly in the mouth and nose healthy. Eating fish like boneless bangus will lessen the probability of having those kinds of sicknesses. Aside from that it tastes good because it is marinated with vinegar and garlic. It is also affordable and easy to prepare; for just P100 you can have three (3) medium pieces of boneless Bangus that is guaranteed fresh. The fact that daing na bangus is deboned, it will be easier and safe to eat especially to kids and adults.

A Social Partnerships in the New Millenium

Social partnership is very fashionable right now. It has become the new â€Å"buzzword† in Industrial Relations. The ‘new' government, the TUC and the CBI are all promoting partnership at work, every week there is another conference held somewhere in the country on the topic of partnership. There is also a huge amount being written about the issue, some Industrial Relations commentators have even hailed this as the most exciting thing to happen to UK industry in years. However, not every group completely agrees with this. For example, some groups believe that Social Partnership has had a very negative effect on British Trade Unions. At www.labournet.org.uk a group have named a bulletin board ‘Solidarity'. It is a page dedicated to ‘challenging social partnership' and it's apparent corrosive effects on union power. It is very typical of the types of arguments put forward by groups that are oh so against social partnerships. Stakeholders like the authors of solidarity believe that social partnerships tie unions to the coat tails of employers. What they want is a ‘new unionism' which opposes subordination to the ‘global market' and builds on the experience of the Liverpool Dockers. This group is completely opposed to any kind of privatisation and really wants more from unions than just a concern for working conditions. They want a break â€Å"..with the narrow work place concerns of ‘non-political' trade unionism† and believe that unions should fight † for the interests of the working class and oppressed as a whole†. They also see a need for a repeal of all â€Å"anti-union† legislation and an end to state interference into unions, such as social partnership agreements. Taken from ‘Solidarity', the journal that openly states it's purpose is to challenge social partnerships in trade unions, here are some ‘facts' that display how social partnerships have had a harmful effect on British trade unions: In Rover and the car industry, where the unions have identified the interests of workers with commercial success in the ‘global market', they have been gravely weakened and meekly accepted massive job cuts. USDAW has reached a ‘Partnership Agreement' with Tesco which takes away the right of the union members as a whole to vote on pay deals. The TUC has collaborated with a privatised utility in the Energy Industry and set up a company with them – Union Energy – thus effectively abandoning the fight for re-nationalisation. They are collaborating with a privatised utility which has decimated trade union members' jobs. The unions have swallowed ‘Investors in People' which identifies the interests of union members with the ‘business aims' of private companies. The TUC and most unions have accepted that the increased competition of the ‘global market' means unity with ‘our employers' and competing with workers in other countries. Stakeholders like these aim to challenge social partnership by campaigning for complete independence of the unions from the employer. They reject globalisation and counterpoise to it a working class internationalism which recognises that workers have more in common with those in other countries than they do with ‘our own' bosses. It is a very Marxist standpoint . They feel that for those in the unions who support their independence from the employers and the state, a systematic struggle against ‘social partnership' in all its manifestations is a central task if they are to break the unions from the employers' coat tails. They are insistent that this outlook has only been adopted by union leaders. It has though percolated down to many workplaces, reinforced by the fear of unemployment. This far left view contrasts greatly with those unions that actually see social partnership in a very positive, if slightly unclear light. Unions like FIET, The International Federation of commercial, clerical, professional, and technical employees see social partnership as a â€Å"new and challenging area of work for the union.† For unions that see the millennium as a time to accept social partnership, it will mean unions and companies learning to do things differently, rather than trying to campaign against this change. Some unions like FIET have accepted that we now have a government committed to promoting the partnership approach, and to ensuring that it becomes a permanent feature in the workplace. Unions like this have therefore accepted that social partnership is going to be around for a long time. I think that left wing reactions to social partnerships, like that of ‘Solidarity' is very much a reactive one rather than considered. I think that those stakeholders set so strongly against this issue need to understand that the government's political commitment to partnership goes far beyond the UK. We now have a new and positive approach to Europe and this social partnership model is at the heart of the EU's approach to all Industrial Relations. Indeed Social Partnership does mean long term changes to the Industrial Relations scene in Europe and in Britain, all that unions need to work on is understanding what these changes will mean for their members and the companies that they work in. Looked at from this more positive, optimistic standpoint then social partnership has the potential to deliver some very real benefits: Potentially it means that employers will be working with the trade unions to bring about improvements in the quality of work. It means that employees, through their trade union, will be given a much greater say in how their company is run. Social partnership should give unions the opportunity to be consulted earlier, more often and on a wider range of issues than has happened before. Surely the growth in partnership at work can only be a welcome one, if not somewhat overdue? However, these encouraging and upbeat pointers can only be achieved if the unions get themselves involved in equal terms right from the beginning, otherwise employers could try to do things without the unions. As stakeholders like ‘Solidarity' state I think that there is indeed a risk that social partnership may be used to try and undermine trade union organisation in the work place. Employers could potentially claim that they can have a partnership directly with their staff and do not require the union's participation. If the unions are excluded in this way then not only could there be disastrous consequences for union members but social partnership will not work for employers either. Partnership can only be successful when employees as partners are properly supported and resourced through a dependable trade union. To illustrate this point further, let us consider what may happen if the retail sector tried to introduce partnership without trade union involvement : Most employees in this sector work part-time. There are increasingly complex and unsociable working hours in retailing which in turn means that most employees may have very little contact with anyone beyond their shift. In these circumstances employees have less of an opportunity to form a collective view. Simply meeting together can be extremely difficult in such organisations, let alone having the resources and confidence to develop their own ideas and concerns. Therefore it is clear that in most cases employees are unlikely to become equal and effective partners when they do not have the time or the means to generate their own agenda. A dependable and experienced trade union means that employees can enter into partnership properly supported and resourced. To achieve this, a real commitment is required from employers to supporting trade union membership, as the best way for their staff to be given a voice and more importantly the confidence to use it. Basically partnership needs partners. But how will social partnership actually change things in real terms for employees and the unions? By answering this question I will hopefully be able to assess if social partnership is a viable way forward in the new millennium. Firstly, unions need to take a positive approach, for them social partnerships should be about: Co-operation, not confrontation. Improving the quality of working life. Employers listening to and respecting unions and vice versa. Employees developing their own agenda through their trade union. If they agree on the above terms then hopefully it will mean: Moving away from the common practice of the union only talking to companies once a year. At the moment, even with companies with whom there exists a good relationship, unions often only talk to the organisation at the time of the annual wage negotiations. Many unions feel that the annual wage round sometimes becomes a little tired and predictable, with companies offering the lowest increase that they feel they can get away with. However, partnership is different. For the unions, it means talking to companies throughout the year. It means having a constant dialogue with employers about what is happening at all levels of the company. It should also mean that the union is consulted on a wider range of issues. Companies are used to contacting unions when they are implementing redundancies or sell offs. Mainly because there is a legal obligation on them to do this, but unions have not in the past been consulted on the overall direction of a company or about strategic decisions that may affect employees. A Social Partnership means that the union should be consulted on a far wider range of issues than they have been used to. It means earlier and better consultation sessions, theoretically no more being told about something when it has already been implemented.

National Victory in the Spanish Civil War Essay

National Victory in the Spanish Civil War - Essay Example The war offered both Hitler and Mussolini an opportunity to test their equipment and military strategies. Hitler also expected Francos assistance in any future German war. Concerned about Hitler’s actions, British and French officials began to discuss an alliance with Soviet Union. But Soviet leader Joseph Stalin felt threatened by Hitler’s military actions and did not think British and French would protect his country. Hence in 1939, the Soviet-German nonaggression pact was revealed where each side agreed not to attack the other. The Spanish Civil War officially came to an end on April 1, 1939, without any reconciliation. Franco began a reign of terror aimed at the physical liquidation of all his potential enemies. Concentration camps were set up and tens of thousands were shot. Mass executions continued until 1944. Meanwhile, World War II was under way, and many of the volunteers took up arms against fascism again (Taylor). Despite almost universal support for the Republic amongst British intellectuals and widespread support amongst the working classes, the British government did not act. It was not only that they feared anything that might lead to a wider war in Europe but also that, British businessmen and a majority of the British Cabinet felt more sympathetic with Franco. Large corporations in America also worked on Francos behalf. In France, the governments sympathies were with the Republic, but the government was weak and feared any acts that might alienate its own military. However, after providing t he Loyalist government with a score of planes, France decided to propose an international policy of Non-Intervention that would bar all foreign aid to Spain (Miller). In fact, if Franco and the rebellious generals had been denied Italys and Germanys aid in the early days of the war, the rebellion might well have collapsed.

World Cinema - Analyze the relationship Essay Example | Topics and Well Written Essays - 750 words

World Cinema - Analyze the relationship - Essay Example Guevara and Alberto witnessed injustices that characterized the world at the time under cruel injustices a fact that led to immense suffering of peasants. Self-discovery is a theme that depicts itself in the movie, with the two friends assuming their identities after their experience during the trip. This paper seeks to analyze the relationship between travel and identity in The Motorcycle Diaries. La Poderosa, meaning the mighty one, was the name of Guevara and Alberto’s motorcycle, which did not successfully complete their journey. Their journey started in their native land, Argentina. The two friends helped each other throughout the journey with medicine and food supplies. They also shared their expenses as well as money. It is through this journey that the growth in the two friends is emphasized. Not only do they stand up for each other, but they also looked into the plight of the disadvantaged in areas they visited. An example is the leper colony that they assisted in Easter Island despite them being cast out far from human contact. They even shook hands with these lepers without wearing gloves despite the risk of contracting leprosy themselves. To prove this, Guevara swims across the Amazon River, which barricaded the lepers from the doctors and nurses in solidarity with the isolated lepers. Their sense of humanity and responsibility also comes to play when they s howed their concern for the dirty and poor state hospitals in Chile, Colombia, Venezuela, and Peru. This shows their journey of self-development, which is evident through their actions. At the start of the journey, Guevara and Alberto are just two young friends who are searching for fun and adventure. They appear as restless, with wild spirits that are imaginative. However, their encounters and reaction to situations that came their way indicate their care for humanity as well as their goodwill. It can be concluded that the journey

Law on Involuntary Manslaughter Essay Example | Topics and Well Written Essays - 7750 words

Law on Involuntary Manslaughter - Essay Example Whereas, an act of involuntary manslaughter is identified as the one that originate from the failure to perform a legal duty expressly required to safeguard human life, from the commission of an unlawful act not constituting a felony, or from the commission of a lawful act in a negligent or improper manner. (Webster's online dictionary, http://www.merriam-webster.com/dictionary/ involuntary%20manslaughter, accessed on 11th April, 2009) According to Encyclopaedia Britannica, manslaughter is defined as: 'in Anglo-American criminal law, a category of criminal homicide that generally carries a lesser penalty than the crime of murder. Different legal systems use different criteria to distinguish the kinds and degrees of unjustified killing'. (Encyclopaedia Britannica, Manslaughter, http://www.britannica.com/EBchecked/ topic/362828/ manslaughter, accessed on 11th April, 2009) In legal context, manslaughter is considered as the unlawful killing of a human being without malice or premeditation, expressed or implied; distinguished from murder, which requires malicious intent. The distinction between manslaughter and murder can be identified as, in the former case, though the act which caused the death is unlawful, either expressed or implied, it is termed as manslaughter, or if committed otherwise, it is termed as murder. Manslaughter also differs from murder because there can be no time for premeditation or preplanning. Manslaughter is voluntary, when it happens upon a sudden heat; or involuntary, when it takes place in the commissioning of some unlawful act. The act of manslaughter becomes voluntary manslaughter if it happens that the defendant had an intention to inflict death or serious injury. But it depends upon the potential liability of the defendant with regard to the circumstances by which the act is committed in relation to the state of mind while the act is done. Provocation or heat of the moment qualifies this. Suppose a husband happens to see his wife sharing the bed with her lover, and in sudden provocation and losing control he commits the killing of his wife, it is termed as manslaughter. (http://www.lectlaw.com/def2/m013.htm, accessed on 11th April, 2009). Precisely, involuntary manslaughter can be identified as an unintentional killing derived out of recklessness or from an act of illegal nature which amounts to misdemeanor. It is a criminally negligent homicide committed with no intention to do it. The decision on Scarlett [1993] 4 All ER 629 illustrates the above distinction. 1. Scarlett [1993] 4 All ER 629 Facts of the Case: The appellant, Mr. John Scarlett, being the owner of Queen's Road Tavern public house in Halifax, was about to close down his tavern on 12th June, 1991 after the day's business, when the deceased, Mr. Larkin approached the appellant for getting service. But the appellant denied service to him. There were some heated arguments over this, and the appellant pushed the deceased towards the doors. They struggled against each other and the only reliable witnesses to this described the appellant's act as 'bundling the

The Different Types of Marketing Strategies Research Paper

The Different Types of Marketing Strategies - Research Paper Example Here, the marketing personnel of any organisation comes in the picture as a foreground and is the backbone of the business. The way the organisation market its products and services make a direct impact on to the firm, its suppliers, its customers and all others that come under affection by the firm’s choices. In addition, marketing is another way of building and sustaining enduring relationships between buyers, sellers, and other parties. Creating, communicating, delivering, and exchange offers are a few of the courses of actions involved in the process of marketing. Nevertheless, a customer has always been a vital and salient entity for the business; therefore, customer value is the prime objective of marketing any product or service. Through marketing, the organisations make sure that the customers get value from the products or services that they are buying so that they can create brand loyalty for their products or services (Mercer, pp. 11-18, 1996). The effective marketi ng concepts make visible the vision of the marketers that they focus on letting people be acquainted with their products and services and win over them to buy or use it on a frequent or recurring basis. Here, the marketing strategy plays a substantial role as it shapes the overall business goals. In addition, the marketing strategy incorporates the business definition, account, or picture of products or services, a silhouette of target customers, and defines the company's role in affiliation to its competitors. Therefore, marketing strategy is a process that the marketers follow as it facilitates the firm in focusing and paying attention to their resources lying on the opportunities. An effective marketing strategy would not only boost the level of sales but could become a leading reason for gaining an edge over the competitors (pp. Pride &  Ferrell, pp. 29-30, 2006). According to the author Seema Gupta, â€Å"strategic marketing is best seen as an  ongoing and never-ending pro cess†.

Essay Question 3 Example | Topics and Well Written Essays - 250 words

Question 3 - Essay Example chists obtain power through it because they can control the public by ensuring that equality on some commodities and activities are championed (Spaaij, 2010). In the second principle, anarchism employs proactive approaches, where they assume that not everyone in society has the ability to get access to the free services offered. Therefore, it is upon those who have to make sure that they share with those who do not have. While people may confuse anarchism and terrorism as being one thing, they are completely two different forms of leadership. Even though both of them employ oppression theories, anarchism tends t o champion for equality and protecting human rights where possible (Fleming, 2000). On the other hand, terrorism, which is motivated by extreme radicalization of religious ideologies, has little thought of what human rights are. They believe dying is the only way through which people can protect the Islamic religion and have an external peace. However, anarchism has varying schools of thought, where individualist anarchism and anarcho-capitalism believe that all natural resources should be privatized. The same case is common in the Middle East countries, where people are allowed to own oil wells, while those who are not lucky are either poor or into other businesses. The other school of thought, which involves libertarian socialism and geoanarchism believe that natural resources should remai n public so that every person benefits from the revenue. Terrorist organizations identified with anarchism include Anarchist Black Cross, Autonomous Action, Foot Not Bombs, and International of Anarchist Federations among others (Book chin, 2005). Most terror groups seem to use anarchism, with the thought that by owning natural resources, especially oil, uranium, and other weaponry mineral will make them superpower militia groups and would control every activity in its boundaries. However, a good thought on anarchism makes it different from what terror groups carry

Japanese Public Broadcaster-NHK Research Paper Example | Topics and Well Written Essays - 1000 words

Japanese Public Broadcaster-NHK - Research Paper Example NHK is no different. All told, NHK has probably never been in such difficulties at any other point in its history. To begin with, it is useful to examine the recent scandal that so dented the reputation of NHK. In late 2004, NHK employed more than 10,000 people and had revenue from a viewing fee that came to almost $5 billion. But then all hell broke loose. Top executives were accused of embezzling funds, and the popular company chairman was forced to step down. NHK came under increased governmental and legal scrutiny, and competitors revved up their engines. This report neatly summarizes the situation: In Japan, the NHK viewing fee (which is something that akin to BBC’s license fee) is mandatory under the country’s broadcasting law. Although there is no penalty for those who fail to pay, almost 80% of about 46 million Japanese TV households make monthly payments of about US$12. The 2004 scandal, however, triggered waves of consumer discontent, resulting in about 1,280,000 refusals to pay. This translates into a total revenue loss of some US$42 million or 7.4% of NHK’s gross revenue for the fiscal year 2005 which ended in March 2006. The percentage of fee-paying consumers dropped by almost 10%.1 That marked only the beginnings of NHK’s financial woes. Two twin problems were approaching on the horizon that will affect NHK’s bottom line for years to come: the financial crisis and recession of 2008-09 and the huge changes in the media world brought about by the Internet. Like everyone else NHK is finding that serious journalism is in trouble. Laborious and expensive, news stories and investigative reports that reflect a passionate commitment to the public interest are being squeezed out of our media by new economic realities. Faced with decreasing advertising revenue, media companies have been consolidating rapidly in recent years, in part to take advantage of economies of scale.  Ã‚  

Assignment on Nokia Essay Example | Topics and Well Written Essays - 3500 words

Assignment on Nokia - Essay Example The Company that has been selected for the study is Nokia. The company is a worldwide leader in the communication industry that has made its presence felt globally. It has stamped its authority through the globe and created an everlasting image in the minds of its consumers. It is interesting to understand that how Nokia has understood and incorporated the various components of creating a unique identity that has made them surge ahead of the competitors. Since Nokia has lead from the front by creating its dominant corporate image, it makes the company an ideal choice for a case study.Company OverviewThe Finnish multinational, Nokia Corporation that is headquartered in Espoo, Finland came into existence in the year 1865, when its founder Fredrik Idestam founded the company. The company mainly focused in manufacturing of mobile devices. It catered to the large market segments including GSM, CDMA and W-CDMA. It also diversified itself into developing internet services and included featu res like music, maps, media and games in its mobile phones. (Moeder, n.d.).The company presently operates in more than 120 countries and its annual global revenue generated is close to â‚ ¬ 50 billion in the year 2008. The company is undoubtedly the world’s largest mobile phones manufacturer with an overall market share of 38% in the Q2 of 2009.The Company has undergone a few conglomerate acquisitions in order to strengthen its foothold in the communication industry. The company acquired Sega in the year 2003, and merged with Siemens.

Motivations for Plastic Surgery Essay Example | Topics and Well Written Essays - 1250 words

Motivations for Plastic Surgery - Essay Example In her article, Balsamo (1992) note two widely pursued perceptions about plastic surgery where a section of critics perceive the practice as â€Å"technological colonization of women’s bodies† while there are those who think plastic surgery presents women with the opportunity to get â€Å"empowered† (226). Central to these two perspectives is the motivation behind the ever-increasing number of women who are willing to go under the knife in order to get what is considered a perfect body. Certainly, not all plastic surgeries are undertaken for cosmetic reasons given that there is also a large section of women who are forced by medical reasons such as breast cancer after mastectomy. One of the areas that have reported a rapid increase in the number of clients is breast surgery procedures. The number of women looking for cosmetic breast surgery has been on a dramatic rise since Timmie Jean Lindsey as the first woman underwent the procedure in 1962. Although the shape of preferred breast implants have been fluctuating depending on the societal trends of specific periods with the 1970s women preferring a teardrop shape while those of the 1990s went for the roundest breasts possible, the global number of those interested in the procedure has always been on the increase (Foster). It is estimated that in Seoul, South Korea’s capital, one out of five women had undergone a plastic surgery procedure (Conley). These figures have continued to increase even with reported health complications such as the Poly Implant Prothese (PIP) scare, which is in fact not the first one. Over the history of cosmetic surgery, there have been always been an alternative to procedures that were deemed as risky such as the 1992 US silicone scare which led to many women going for plastic surgery to prefer saline instead of silicone implants. The risks on physical health such as possible infections, chronic pains, numbness of affected areas, breakage, leakage as well as necrosis for those who go through such procedures have deterred potential clients.     

Comparative Study Of Corruption Study Essay Example for Free

Comparative Study Of Corruption Study Essay ABSTRACT   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Having Nordic countries consistently on top of the CPIs least corrupt countries for years, there must be something in this culture and tradition that make them highly regarded as having a clean and honest government. Based on the 2006 Corruption Perception Index, Finland and Iceland are the top two least corrupt countries while Haiti and Burma hailed as the two most corrupt countries in the world. This paper aims to find the reasons why these countries were in their current position in the CPI by comparing their government system, culture and tradition. This paper also aims to find solid evidences that will prove that the culture of corruption is not a matter of effective and efficient policies but on the culture of strict implementation of such policies, the moral and ethical standards of the people and the collective concern of the people to their country.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   A brief background of the 2006 CPI report is included in the first part of this paper. A separate section, discussing thoroughly the different elements which may contribute to each country’s culture of corruption is the main focus of this paper. Data from competent writers and qualified analysts were compared in order to make readers further understand the economic, political and social status of each country. A brief conclusion is also included, summarizing the main points of comparison between countries. BACKGROUND ON CPI’s 2006 RESULTS   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   In the 2006 Corruption Perception Index, Finland emerged on top as the least corrupt country in the world, scoring 9.6 out of the 10 clean score. Scoring equally are Iceland and New Zealand. In the CPI 2006 published by the Transparency International, Haiti turned out to be the most corrupt of the 163 countries involved in the survey scoring only 1.8 while slightly on top is Myanmar with 1.9 score. If we are to look into the previous CPI results, we can see that the top Finland and other Nordic countries, Iceland and New Zealand have been consistently on the five least corrupt countries. The question here is who or what makes a country the least or the most corrupt country in the world? â€Å"The CPI is a composite index which uses survey results from business people and country analysts as with their assessment and perception of corruption among public officials and political figures† (J.G. Lambsdorff). This means that the CPI is considered as a competent and reliable material considering that it makes use of qualified people in assessing the existence of corruption. It utilizes different sets of polls relative to perception of corruption, had them compiled and analyzed before it came up with the figures published in the CPI. In 2006, Transparency International made use of 112 sets of polls and survey from independent bodies listed below:   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Freedom House: â€Å"Nations in Transit†   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Economist Intelligence Unit   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   United Nations Commission for Africa   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   World Economic Forum   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   World Markets Research Center (London)   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Merchant International Group Limited (London)   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Political and Economic Risk Consultancy (Hong Kong)   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   International Institute for Management and Development (Laussane)   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Country Policy and Institutional Assessment (IDA and IBRD of World Bank)   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   It is also important to note that bribery among public officials and servants is one of the major factors considered by analysts as the major indicator of corruption. â€Å"Political culture and political institutions determine the level of corruption† (P. Tiihonen). It is therefore but fair enough to conclude that corruption begins when bribery is tolerated by anyone in the government or any public office. To have a deeper understanding of corruption, we will try to compare two of the most corrupt countries in the world with that of the two least corrupt countries using different areas and aspects. By doing so, we will be able to assess what factors make Finland and Iceland’s government clean and the factors that brought Haiti and Myanmar on top of the list of the most corrupt countries. ELEMENTS THAT MAKE A COUNTRY CLEAN OR CORRUPT Government and Political System   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Finland has the culture of good governance. Based on the political structure of Finland, we can say that it has one of the best, if not the best system of government. First, Finland is a country that does not recognize social class. This is what they referred to as â€Å"Egalitarian Society† where everyone, regardless of social status is given equal opportunity to avail of the services of the government and to be of service to the people (Tiihonen). Education is compulsory, women are given the full rights for suffrage and political participation as candidates, pension is provided for all citizens who reached 65 years old, healthcare services are free for everyone and education is free from basic to higher education. If all people are able to experience this kind of welfare in their country, it would be far from their means of finding comfort to bribe and accept bribe. Nordic countries like Finland and Iceland live up to their political culture of transparency and corruption free society2. Considering the legal framework of Finland, one can immediately conclude that their government is serious with combating corruption as bribery, which includes both giving and accepting bribe, is a criminal offense (Criminal Code: R1 101/19.12.89). For them money, jewelry, household, special or low interest loans, trips, honorary titles and recommendations are forms of bribes (J. Brady). Nordic countries also have the collective decision structure, wherein decisions are in the hands of a collegiate body making hard for bribery to be tolerated. In complete contrast, Haiti is a country of faltering democratic institutions and unstable political situation making it the poorest country in the Americas5. Recent reports involved government officials in the issue of drug trafficking, particularly the Presidential Security Unit and the Palace Guard4. Reported incidents of violence against anti-government demonstrators, said to be demanding to better public services like water and highways, are clear indicators of the country’s political instability. Growing counts of human rights violations and the Aristede’s government’s disrespect for the people’s freedom of expression are regarded by analysts as â€Å"political humanitarian catastrophe† (J. Regan). Another indicator of the country’s unclean government is the incident of credit union pyramid scheme involving banks which money allegedly came from drug money. It turned out later that the scheme is a scam where the government promised to pay depositors who lost $200 million dollars and so far has not yet been fulfilled6. As with Myanmar, political instability is not too obvious as that of Haiti.   A political observer, in his article entitled â€Å"Magnificent, Troubled Myanmar† the writer described the country as â€Å"beautiful, tragic, natural, and chaotic place†7. In his article, he made mention of the people’s fear of the government by strictly avoiding discussion or making comments about their government even by merely consorting foreigners. In this situation, we can say that freedom and civil liberty is not honored by the government of Myanmar. As with corruption, the author stressed the severely low income of the people of the country, with as low as half a dollar per day for most citizens. Considering their 883% literacy rate, this is a tragic economic situation. Based on this situation alone, corruption, especially bribery is highly expected. In fact, Myanmar’s public servants have negative real earnings (M. Maung). According to Maung, the iniquities in Burma today are driving its people into corruption. Such iniquities include: 9the growing power and wealth of the military rulers at the expense of impoverished masses, the sub-human conditions and plight of hundreds of thousands of displaced refugees stranded along Burmas borders. Ethical and Moral Standards   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   In Nordic countries like Finland and Iceland, to be a public servant means to of real service to the public. Civil servants in these countries take pride of being a member of a generally honest government. For Finnish society, having a good name means a lot so they really do their best to avoid being accused of any malpractice especially that of related to dishonesty (P. Tiihonen). The Finnish society also maintained their administrative culture of creating efficient civil servants by reserving senior civil service post to lawyers or at least those who earned degrees in law10. The government of Finland also gives its civil servants the responsibility for every decision and action they make. They are left independent in their tasks and do their individual duties with the least supervisory intervention. This is the reason why Finnish government employs highly-educated individuals in the civil service posts11.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Highly in contrast is the situation in the Burmese civil society. In a country as poor as Burma, to accept bribe is a matter of practicality. Bribery is normal in their everyday life where even the service of a lineman needs bribe. Accepting bribe for them is of being resourceful7. Like the people of Burma, Haiti citizens are evidently of low morale since most of them do not take courage to express their dislike and frustrations to their government. The continuing reports of chaos and demonstrations of few brave citizens are indications that these people resort to violence just to seek for the government’s attention. Quality of Life   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Finland is a moral and welfare society where almost everyone enjoys a comfortable life. With free education, pension, health care benefits and honest and dedicated civil servants, I would say that Finnish people might have been the luckiest people in the world. They enjoy their civil rights and political freedoms especially in participating in public issues. For them, everything that concerns the public must be open to all citizens. This means that they are all given the right to question any government policy or decision. Even diaries and records concerning public transactions are literally open to everybody2. Finland also takes pride of their culture of being environment friendly. For them, taking care of their natural resources are powerful means of maintaining their economic edge. As evidence Finland still tops the Environmental Sustainability Index along with Norway, Canada and Sweden11. Considering violence in Haiti and the severe poverty in Burma, it is evident that their citizens are far from enjoying a good quality of life. Political instability, rampant and open bribery, environmental degradation and disrespect of individual freedom are the frustrating realities of life of the people of Haiti and Burma. With widespread unemployment and a negative real wage for most people, Burma is a picture of a real poor country whose government does not seem to care for its people. CONCLUSION   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   By comparing the two least corrupt and two most corrupt countries in the world, based on the 2006 Corruption Perception Index, we were able to have an idea of how these countries differ on several areas. In our analysis of such areas we were able to draw some information that relates to their system of government and their philosophies which somehow define their stand in the issue of corruption. To summarize the major points of comparison, Nordic countries like Finland and Iceland have the following philosophies for a corruption-free society: Nordic countries strictly do not tolerate dishonesty especially corruption, a principle they call â€Å"ethicality.† Finland and other Nordic countries strictly implement transparency on public records and transactions by literally opening all pubic documents to every citizen. The government also opens its door to criticisms and regard public administration as privilege being a member of an honest and highly regarded circle of civil servants. The Finnish government’s collective decision structure makes it hard for bribery and corruption to enter into the system. Nordic countries maintain a low hierarchical structure where civil servants are highly educated and were left independent and individually responsible for their decisions and actions. This structure also encourages civil servants to maintain a good status in the society by having a clean name. Nordic countries’ legacy of egalitarian society ensures that every citizen enjoys the benefits of being a citizen of a moral and welfare society.   In contrast, this paper have presented the proofs of Haiti and Burma’s political instability, severe poverty, absence of political and civil rights and the government’s lack of concern for its people as causes and at the same time indicators of their corrupt government. By comparing the political and economic situations of the four countries, we were able to find out that corruption is not a matter of policy and laws but the strict implementation of it. Also, that poverty is not an indicator of corruption but a reflection of it. Making Finland as a perfect example, the world must make considerable efforts in implementing its laws and begin to nurture an honest society starting at the public administration. REFERENCES    1Transparency International.â€Å"Corruptions Perception Index 2006†. Retrieved on July 14, 2007 from http://www.transparency.org/publications/gcr/download_gcr#19 2â€Å"Nordics Least Corrupted Nations in the World† Retrieved on July 14, 2007 from http://www.scandinavica.com/culture/society/corruption.htm 4â€Å"Jamaica Still Leading Caribbean Drug Route†CNN News. March 01, 2003. Retrieved on July 14, 2007 from http://www.cnn.com/2003/WORLD/americas/03/01/drugs.caribbean.reut/index.html 5â€Å"Haiti Tops World Corruption Table† BBC News. November 06, 2006. Retrieved on July 14, 2007 from http://news.bbc.co.uk/2/hi/business/6120522.stm 6â€Å"Aid To Haiti is Unfrozen, but Corruption and Chaos Remain† Retrieved on July 14, 2007 from http://www.allbusiness.com/central-america/289066-1.html?yahss=114-2974554-289066 7â€Å"Magnificent, Troubled Myanmar† Retrieved on July 14, 2007 from http://www.vagabonding.com/travelogue/000038.html 8â€Å"Myanmar† Retrieved on July 14, 2007 from http://www.infoplease.com/ipa/A0107808.html 9Maung, Maya. â€Å"The State of Burmese Economy under Military Management† Retrieved on July 14, 2007 from http://www.ibiblio.org/obl/docs/HRDU%201995/The%20state%20of%20Burmese%20Economy.htm 10Brady, Joe. â€Å"Corruption-Nearly None at All† Retrieved on July 14, 2007 from   http://virtual.finland.fi/netcomm/news/showarticle.asp?intNWSAID=25892 11Tiihonen, Paula. â€Å"Good Governance and Corruption in Finland† Retrieved on July 14 2007 from http://virtual.finland.fi/netcomm/news/showarticle.asp?intNWSAID=25891 Lambsdorff, Johann Graf. â€Å"The Corruptions Perceptions Index 2006†. Pages 324-330 Lavers ,Tom. â€Å"The Global Corruption Barometer† pg. 13 â€Å"Finland Ranks as Least Corrupt† CNN News. October 08, 2003. Retrieved on July 14 2007 from http://www.cnn.com/2003/BUSINESS/10/08/corruption.index/index.html

Staphylococcus Aureus: Structure and Functions

Staphylococcus Aureus: Structure and Functions Introduction 1.1 Staphylococcus aureus Staphylococcus aureus is an opportunistic yet versatile pathogen that can infect almost all types of tissue in the human body. 33-50% of healthy individuals were reported to be S. aureus carriers. The diseases resulting from S. aureus infection range from superficial infections; invasive infections such as endocarditis to the life threatening septic shock and toxic shock. The presence of foreign material greatly increases the risk of infection by providing a base for attachment and biofilm formation. S. aureus appears as clustered gram positive cocci under the microscope. Criteria used to identify this organism include the production of golden pigment on nutrient agar; being positive for coagulase; mannitol fermentation and the production of deoxyribonuclease. The virulence of the infecting strain and the nature of the host immune response are important determinants for the outcome of severe S. aureus infection . 1.1.1 S. aureus genome and regulation of gene expression S. aureus has a 2.8-2.9 Mbp circular genome. House-keeping genes and genes associated with central metabolism and some virulence determinants (e.g. protein A) are highly conserved among strains and make up the majority of S. aureus genome. The rest more variable regions mainly consists of mobile elements such as pathogenicity islands (SaPI, 7 identified), genomic islands (ÃŽ ½SaÃŽ ± and ÃŽ ½SaÃŽ ²), Staphylococcal chromosomal cassettes (SCC) and bacteriophages. S. aureus expresses an array of adhesins, immunomodulatory molecules; anti-inflammatory proteins and as many as 30 toxins to invade, evade and cause host tissue damage. Many of the virulence factors discussed below are encoded by genes located in the variable region. Their expression is under the control of a complicated and interconnected regulatory network . Four main gene regulators have been identified, including the two component regulatory system (agr, sae); the transcription factors (SarA and its homologous); the nutrient regulated CodY regulator and alternative transcription factor ÏÆ'B. agr is an auto-inducible quorum-sensing system, promoting expression of extracellular virulence factors and down-regulating cell surface proteins. ÏÆ'B has been shown to participate in the general stress response, and may be involved in antibiotic resistance; pigmentation; biofilm and micro-colony formation (referenced in ). Many surface proteins/adhesin have been shown to be positively influenced by ÏÆ'B, while the expression of most exoproteins and toxins were down-regulated. Activity ofthe agr system is influenced by other gene regulators and may be regulated by cell density. The transcription of agr components were found to be promoted by SarA and gene products of the sar locus and repressed by CodY. To add up the complexity, transcription o f the Sar locus was controlled by three promoters that can be differently activated during in vitro growth. One of these promoters was demonstrated to be ÏÆ'B dependent . It is generally regarded that exponential growth in vitro is correlated with the colonization phase of infection. Correspondingly, genes encoding surface proteins were found to be expressed earlier, starting during the transition from stationary to exponential growth while the expression of secreted proteins started at late-exponential growth phase. The in vivo situation of infection is likely to be more dynamic. Different stimuli trigger combined and coordinated action of the regulatory network, reflecting the particular state of bacterial growth, host defense and environmental nutrition. For example, phagocytosis by neutrophil triggered differential expression of 21.8-39.1% of S. aureus genes â€Å"at any time† following the event. The suppressive effect of CodY on S. aureus virulence factors lead to the possible suggestion that S. aureus may maintain its virulence factor to low level to ‘co-exist harmlessly with the host until a invading opportunity arise. In any case , it would be interesting to see how host immunological activity ‘feedback on S. aureus regulation of its virulence factors, especially immune evasion molecules. 1.1.2 Antibiotic resistance The rapid spreading of antibiotic resistant S. aureus strains through human communities presents a major challenge for conventional treatment. In 2005, it was reported that methicillin-resistant S. aureus (MRSA) infection caused more death than AIDS in USA. S. aureus demonstrated amazing ability to â€Å"co-evolve† with the development of antibiotics. The first generation penicillin uses ÃŽ ²-lactam to bind penicillin-binding proteins (PBP, bacterial transpeptidase) and inhibits bacterial cell wall synthesis. S. aureus resists this class of antibiotics by producing ÃŽ ²-lactamases (aka penicillinase) that cleaves ÃŽ ²-lactam. Second generation of penicillin, such as methicillin was developed. The structure of their ÃŽ ²-lactam has been modified to resist ÃŽ ²-lactamases. S. aureus soon acquired the mecA operon that encodes a modified PBP (PBP 2a), which showed reduced susceptibility for ÃŽ ²-lactam and thus granted resistance to all ÃŽ ²-lactam containing antibiotics. mecA is located on the staphylococcal chromosome cassette mec (SCCmec), a mobile genetic element that allows horizontal transfer of mecA between strains. MRSA infection shows increasing prevalence in all continents, primarily in healthcare-environments (HA-MRSA). Alarmingly, these strains have been shown to exhibit resistance to other types of commonly used non-lactam antibiotics such as ciprofloxacin and erythromycin. Vancomycin, a peptidoglycan polymerization inhibitor, is now considered as the last-line antibiotics for MRSA treatment. However, strains of vancomycin-intermediate S. aureus (VISA) have emerged. Notably, these strains have developed thicker cell walls that require higher concentrations of vancomycin to be effective (minimal inhibitory concentration MIC over 4ug/ml). A vancomycin resistant S. aureus (VRSA) strain has been reported recently (MIC >32 ÃŽ ¼g/ml). This complete resistance is most likely due to the horizontal transfer of the vancomycin resistant gene (VanA) from En terococcus faecalis. Development of effective new antibiotics against S. aureus has met with only limited success, urging the development of alternative therapies based on better understanding of the pathogenicityof S. aureus . 1.2 Adhesin / ECM interaction as key to S. aureus colonization/invasion Colonization is always the first step in bacterial infection and is an important component in pathogenesis. The wide range of tissues that S. aureus can infect reflects its ability to adhere and therefore colonize many different biological niches. S. aureus is now recognized as an invasive organism, targeting non-professional phagocytes such as keratinocytes, epithelial cells, endothelial cells and osteoblasts. The tasks of initial colonization and invasion are assisted by S. aureus surface anchored and secreted adhesive molecules known as MSCRAMM, microbial surface components recognizing adhesive matrix molecules and SERAM, secretable expanded repertoire adhesive molecules. The majority of MSCRAMM and SERAM bind extracellular matrix (ECM) proteins such as fibrinogen and fibronectin. In general, the interaction with ECM proteins is regarded as providing a ‘foothold for S. aureus to establish and to exacerbate infection. However, it has been reported that in some animal models l oss of fibronectin binding proteins (FnBPs) led to an increase in bacterial virulence, indicating a role of the ECM protein in limiting bacterial dissemination or enhancing bacterial clearance. Due to overlap in target specificity; functional redundancy and the difference in experiment settings, the exact contribution of each isolated staphylococcal adhensin protein remains ambiguous. Nevertheless, fibronectin (Fn) and fibrinogen (Fg) are the most popular targets of known S. aureus adhesins. The interaction between FnBPs and Fn is thought to play a key role in S. aureus internalization by non-phagocytic cells, as FnBP-coated latex beads and non-invasive bacteria expressing FnBPs were readily taken into the human cells (293 cells). Internalization provides several benefits for the bacterium: firstly, protection from host serum defense mechanisms and antibiotics ; secondly, access to nutrient-rich environments after escape from phagocytic vessels; thirdly, facilitating the crossing of the endothelial/epithelial layer and spreading of the infection; and lastly, establishing intracellular bacterial reservoirs for recurrent infection. S. aureus produces two related FnBPs (namely A and B) that contain almost identical Fn-binding domains in the close proximity to their cell-wall-spanning domain. The Fn-binding repeats of FnBPA were crystallized in complex with the N-terminal F1 modules of Fn. FnBPA peptide is inserted along the triple-stranded ÃŽ ² sheets of the Fn F1 module to form an antiparallel tandem ÃŽ ² zipper. Since the C-terminus of Fn interacts with ÃŽ ±5ÃŽ ²1 integrin that are expressed on most host cell surfaces, S. aureus can attach to the host cell through a Fn bridge. The attachment was shown to trigger the accumulation of actin and focal-contact-associated proteins (e.g. tensin) at the bacteria contact site and initiate internalization in a protein tyrosin kinase FAK-dependent manner. It was predicted that one FnBP can bind six to nine Fn molecules. This multivalent interaction was suggested to be important in mediating internalization . The bindings of Fg by the clumping factors (ClfA and ClfB) and FnBPA are mediated by a shared protein structure called the A domain and by a â€Å"dock, lock and latch† mechanism. Interestingly, Clf A is expressed during stationary phase and binds to the ÃŽ ³ chain of Fg. ClfB is expressed at the exponential growth phase and binds to the C-terminus of Fg AÃŽ ± chain. This portion of Fg has been reported to be involved in the coagulation process and wound healing . Fn and Fg interactions have been blamed particularly in S. aureus wound infection and infective endocarditis in humans. Fg binding alone could initiate experimental endocarditis in mice and has been correlated with valve colonization. However, cell invasion and persistence of the infection only occurred when the Fn-binding ability was enabled (via FnBPs). Both interactions were statistically correlated to disease severity. Binding to Fg and Fn simultaneously significantly accelerated the rate of internalization into cultured endothelial cells. In this regard FnBPA that is capable of binding both proteins may play an important role in establishing endocarditis . Platelets accumulation on the heart valve is another critical factor for the development of infective endocarditis. S. aureus-induced platelet aggregation is a complicated and multifactorial process and was suggested to be dependent on Fg or fibrin. FnBPA, ClfA, ClfB and SdrE (serine-aspartate repeat protein) were shown to be able to cause platelet aggregation independently of other S. aureus surface proteins. ClfA displayed the strongest aggregation effect among the last three. SdrE required the presence of plasma to cause aggregation, although the mediator was not identified. ClfA was proposed to interact with platelet indirectly through an Fg bridge or directly with platelet surface protein p118. Other studies have argued that ClfA-specific IgG also participated in platelet activation by cross-linking ClfA to platelet FcÃŽ ³RIIa receptor . 1.3 S. aureus toxinsdirect damage of host cells S. aureus produces a range of cytotoxins, including the ÃŽ ² barrel pore forming toxin (e.g. ÃŽ ± hemolysin); the two component pore forming leukocidins and the exfoliative toxin. Besides the effects of reducing viable phagocytes and weakening host immune system, S. aureus cytotoxins are currently believed to contribute to bacterial dissemination. Lysis of host cells might also provide nutrients for proliferating bacteria, especially iron from hemolysis . These toxins have different prevalence in different diseases. Exfoliative toxin (ET) operates at the epidermal layer of the skin and causes staphylococcal scalded-skin syndrome. ET-A acts as serine protease and specifically cleaves Desmoglian-1 (Dsg-1). Dsg-1 is a cell-cell adhesion molecule expressed on epidermal keratinocytes. Cleavage of Dsg-1 disrupts the superficial layer of epidermis and helps bacterial invasion. ÃŽ ±-hemolysin (Hla) is strongly implicated in S. aureus lung infections. Active and passive immunization of Hla strongly protected mice against S. aureus pneumonia. Hla is released as a water soluble monomer and oligomerises on the host cell membrane to insert the hydrophobic stem domains. Seven Hla monomers are required to form a pore which eventually leads to cell lysis. At sub-lethal concentrations of Hla, host cells produce pro-inflammatory cytokines like IL-8; IL-6; vasoregulators (PGI2, PGE2 and thromboxane), which could have detrimental systemic effect. The exp ression of twenty S. aureus virulence factors were disrupted individually or in combination and the virulence of the resultant deletion mutants were compared in a mice pneumonia model. Deletion of argA, which encodes a component of the arg gene regulation system, resulted in almost complete loss of virulence. Only the Hla deletion mutant produced comparable effects, indicating the importance of Hla in causing lung tissue damage. Human neutrophils can resist Hla lysis but these cells are targeted by Leukocidins. Leukocidins are thought to act in the similar way as Hla. Among the leukocidins, Panton-valentine leukocidin (PVL) is found in all CA-MRSA (community acquired-MRSA) isolates and strongly associated with CA-MRSA infection. However in mouse models of abscess, sepsis, and pneumonia, the severity of diseases caused by PVL- deletion strains were not significantly different from that caused by the wt strains. More surprisingly, PVL-expressing S. aureus strains did not lyse human ne utrophils better than that without PVL. However, it is not clear how these experimental conditions resemble the amount and time of PVL production during infection in human. Another significant problem is that PVL might be human specific and might not work in mice. Nevertheless, a new class of leukocidal molecules, the ÃŽ ± type phenol-soluble modulin (PSMÃŽ ±), was produced at a considerably high level by CA-MRSA. They were shown to contribute to the increased neutrophil lysis, skin lesion formation and mortality rate of experimental animals caused by CA-MRSA infection . 1.4 Interaction of S. aureus with host immune system 1.4.1 Brief overview of host defense against S. aureus Host defense against S. aureus mainly relies on the innate immune system, in particular, neutrophil mediated killing. The integrity of skin and mucosal layer is the first line of defense against invading bacteria. They also encounter antimicrobial substances released by epithelial cells and phagocytes (e.g. defensins; cathelicidins and lysosome). Defensins and cathelicidin are positively charged antimicrobial peptides that could permeate the bacterial membrane. Lysozyme is produced by many cell types and secreted into various tissues. It cleaves bacterial cell wall peptidoglycan at ÃŽ ² 1-4 glycosidic linkage between N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG). Innate pattern recognition receptors (e.g. Toll-like receptor 2) and immunoglobulin also detect the presence of S. aureus. The latter is recognized by C1q and initiates the complement classical pathway (CP) or directly activates phagocytosis through Fc receptor expressed on neutrophils or monocytes. The human comp lement system is discussed in more detail below. One outcome of complement activation is the production of anaphylatoxin C3a and C5a. Together with formyl methionine peptides produced by bacteria, these chemoattractants are sensed by their receptors expressed on leukocytes and attract leukocytes to the sites of infection. Leukocyte recruitment is accomplished through highly coordinated interactions between adhesins on leukocytes and endothelial cells. Leukocytes change from rolling in the blood stream to firm adhesion to the endothelium and then transmigrate through the endothelial layer. Subsequent migration of leukocytes to infection sites is mediated by integrin interacting with ECM proteins. Once they reach the infection site, the phagocytes recognize antibodies or complement fragments deposited on the bacterial surface through their respective receptors. Phagocytosis then occurs. The phagosome is fused to the lysosome to form the phagolysosome for enzyme-mediated and oxygen fre e radical mediated destruction . 1.4.2 The human complement system The human complement system is a sequentially activated proteolytic cascade that involves more than 30 fluid phase and surface bound proteins. It is one of the key elements of the innate immune system that connects bacterial recognition, leukocyte chemotaxis; phagocytosis as well as adaptive immunity . Three main activation pathways are utilized to recognize foreign and danger signals. The classical pathway (CP) senses antigen bound antibody by C1q. Bacterial carbohydrate ligand is recognized by mannose binding lectin (MBL) or ficolins and initiates the lectin pathway (LP). Upon ligand recognition, both pathways use their specific proteases to cleave C4 and then C2. The resultant C4b2a (the C3 convertase) converts C3 to C3a and C3b. The Alternative pathway (AP) starts by direct binding of C3b to the bacterial surface generated by spontaneous lysis of C3 to C3b called â€Å"tick-over†. Factor B that associates with surface-bound C3b is subsequently cleaved to Bb and forms the alternative pathway C3 convertase C3bBb. The amplification loop of C3 activation is started. C3 cleavage is the central event and merging point in the three pathways. Accumulation of surface bound C3b changes the substrate specificity of C3 convertase to C5. C5 cleavage produces C5a and C5b. The latter m ediates the formation of the membrane attack complex C5b-9 (MAC), which inserts into the target cell membrane and ultimately causes lysis of target cells. C3a and C5a are powerful anaphylotoxin that trigger neutrophil homing. The overall picture of this complex system is depicted in Fig. 1.1 MASP: mannose-binding lectin–associated serine proteases. Figure adapted from Walport et al 2001 (Ref.). Three main outcomes of complement activation are: 1, chemotaxis of leukocytes via C5a and C3a; 2, C3b mediated phagocytosis via complement receptors on phagocytes; and 3, lysis of bacteria by MAC. It is also suggested by recent studies that the C3b presented on bacterial surface are critical factors for B cell activation and the production of specific antibodies. Although the MAC complex cannot function on gram positive bacteria like S. aureus, leukocytes mediated killing is critical for fighting against S. aureus infection . 1.4.3 S. aureus Immune evasion molecules 1.4.3.1 Resistance to antimicrobial substances S. aureus circumvents antimicrobial substances by three main strategies: 1, changing surface charges; 2, modifying the substrates of antimicrobial substances and 3, inactivating antimicrobial substances. S. aureus employs two enzymes to change the highly negatively charged teichoic acid in its cell wall (WTA). DltABCD (Dlt operon) adds D-alanine to WTA and the multiple peptide resistance factor F (Mprf) participates in the modification of membrane phosphatidylglycerol with L-lysine. Both modifications increase bacterial surface charges and thus reduce the attraction to the cationic defensins. dlt or MprF defective strains were killed more efficiently by neutrophil oxygen-independent killing. The former was much less able to cause arthritis and mortality in mice sepsis and arthritis models . S. aureus avoids lysozyme cell wall cleavage by modifying its cell wall peptidoglycan. O-acetyltransferase (OatA) was proposed to mediate this response. OatA catalyses the acetylation of muramic acid, which results in the addition of an acetyl group on S. aureus peptidoglycan. An oatA- strain was sensitive to lysozyme, while complementary expression of the enzyme restored its resistance . Two enzymes have been reported to directly inactivate antimicrobial peptides. Aureolysin (a metalloproteinase) could cleave and therefore inactivate cathelicidin LL-37. Staphylokinase (SAK), a secreted plasminogen binding protein, was reported to form a complex with ÃŽ ± defensin and almost completely blocked its antimicrobial activity. This activity was independent of plasminogen binding. S. aureus strains that produce SAK had a higher survival rate in vitro and higher virulence in a mouse arthritis model . 1.4.3.2 Prevent phagocytosis and opsonision 1.4.3.2.1 General anti-opsonin molecules S. aureus clinical isolates produce a capsular polysaccharide outer cell wall. Serotypes 5 and 8 of the capsular polysaccharide are associated with increased virulence. The capsule is anti-opsonic via blocking of surface deposition of opsonins and their receptor/ligand interaction. Immunoglobulins are targeted by protein A (SpA) and its homologues Sbi (S. aureus IgG-binding protein), SSL7 (Staphylococcal superantigen-like protein 7) and SAK. SpAis a 42 kDa surface anchored molecule. It has four to five IgG binding units that could interact with IgG Fc portion. This interaction presents IgG to leukocytes Fc receptor in the wrong orientation and therefore prevents recognition. In the present of IgG, strains expressing high level of SpA were shown to be more resistant to leukocyte phagocytosis than SpA-poor strains, especially when the sole source of opsonin was purified IgG. Opposite results occurred with IgG-deficient serum, indicating SpA confers protection against neutrophil through IgG interaction. Sbi contains two IgG binding sites at the N-terminal domain. The significance of the Sbi/IgG interaction remains to be fully established. SAK forms a complex with plasminogen and converts plasminogen to plasmin. Plasmin cleaves IgG and C3b deposited on S. aureus resulting in reduced recognition by phagocytes and likely impaired initiation of C1q mediated CP activation . 1.4.3.3 Complement inhibition S. aureus is now recognized as ‘a master of complement evasion. Unlike other bacteria which use host factors to ‘disguise the bacteria or inhibit complement activation, S. aureus produces a group of proteins to attack the key elements of the complement cascades. The list of anti-complement virulence factors is growing. So far, five complement inhibitors have been demonstrated and well characterized: SCIN; Efb; Ehp; SSL7 and Sbi. Interestingly, SCIN, Efb, Ehp and Sbi all use a triple ÃŽ ± helix bundle as their functional domain while their modes of action are markedly different (Fig. 1.2). SSL7 belongs to the SSL protein family. Its function will be discussed in context with other members of the family in a later section. 1.4.3.3.1 SCIN SCIN (staphylococcal complement inhibitor) is a human-specific 9.8 kDa secreted protein with a trip ÃŽ ± helix structure (Fig. 1.2) and is produced by 90% of S. aureus strains. SCIN was shown to inhibit all three complement activation pathways. In the presence of SCIN, the deposition of C3b and MAC were prevented, so was the C2b and Ba release. However the amount of surface bound C3 convertases (both forms) were increased, suggesting SCIN had a stabilizing effect on this complex. SCIN bound to surface-immobilized C3b directly and the binding site was predicted to involve the C3b MG7 and MG8 domain and the area nearby. This was confirmed by the co-crystallized SCIN-C3bBb complex. In vitro binding studies suggested the complex was likely to form in a 1:1 or 2:2 ratio. Indeed in the crystal structure, the complex appeared as a SCIN2C3b2Bb2 heterodimer that was bridged by the two SCIN molecules cross-linking the two C3b fragments. However this cross-linkage was not critical in SCIN compl ement inhibition as monomeric interaction also resulted in stable and inhibited C3 convertase. Native C3 could still associate with the SCIN-C3 convertase complex, but the production of C3b was largely inhibited, suggesting the convertase was likely trapped in a dysfunctional yet stable state by SCIN. Moreover, SCIN exerted a partial competition for factor B binding to C3b and a complete competition for factor H/C3b binding. The significance of the inhibition on factor H was not clear although reducing iC3b (inactive product of the cleavage of C3b) mediated downstream signaling could be beneficial for the bacterium. Physiologically, C3 convertase decays shortly after assembly. This disassociation is required for further cleavage of C2 and factor B. Thus SCIN functions by preventing C3 convertase decay; hindering conformational activation of C3 convertase and possibly by blocking C3b/iC3b mediated signaling . 1.4.3.3.2 Efb Efb (extracellular fibrinogen-binding protein) and the recently discovered Ehp (Efb-homologous protein aka Ecb) have been shown to inhibit C3b deposition in AP and C5 convertase activity in all three pathways. The efb gene is present in 85% of S. aureus isolates sequenced to date. Its inhibitory effects on complement mediated lysis and neutrophil activation in response to C5a have been demonstrated. The Efb complement binding domain (Efb-c) is also a triple ÃŽ ± helix huddle, although the arrangement is different from SCIN (Fig.1.2). It binds both C3 and C3b via the C3d fragment. However, which of the C3 forms is the primary target of Efb is debated. Structural-biochemical analysis suggested the binding affinity of Efb-C to native C3 was higher than that to C3b. The binding was proposed to induce conformational changes in C3 and prevent proper cleavage of the molecule. This view was challenged by Jongerius et al based on the observation that C3 cleavage was not influenced by Efb-C in CP/LP. Instead, they suggested Efb-C attacked complement intermediates that contain C3b. Therefore, in CP/LP, C3 convertase (C4b2a) was not affected by Efb but C5 convertase (C4b2aC3b) was inhibited, as evidenced by the decreased C5a production. Ehp was found to contain two C3d binding sites and showed higher levels of inhibition compared to Efb, though the mechanism of action was proposed to be similar. Nevertheless, the C3d fragment carries another important task: mediating interaction with complement receptor 2 (CR2) on B cells and facilitating B cell activation. Both Efb-C and Ehp were shown to completely inhibit C3d:CR2 interaction and its stimulatory effect on a B lymphoma cell line. The predicted binding site of CR2 on C3d was in close proximity to the residues that have been shown to be involved in Efb-C:C3d and Ehp:C3d binding. The exact competition mechanism remains to be confirmed . 1.4.3.3.3 Sbi Sbi is another secreted S. aureus protein that targets C3 activation. Sbi binds C3b but has a stronger affinity to C3dg. The binding was shown to be improved when the C3a domain was also present. These observations suggested the C3dg and C3a portion of C3 were important for Sbi/C3 interaction. By comparing binding profiles of different domains of Sbi, the C3 binding site was proposed to be located in its fourth domain (Sib IV). Interestingly, Sbi IV alone inhibited AP activation in a dose-dependent manner. However when the third domain was also present, incubation of human serum with this recombinant protein induced activation of complement, as shown by the degradation of native C3. A distinctive C3 derivative was present in Sbi-III-IV treated serum, whose molecular weight and migration behavior on two dimensional SDS-PAGE correspond to a transacylation product of C3b and Sbi. The cleavage of C3 activates an internal thioester moiety in the C3b fragment, which allows C3b to form cova lent bonds with hydroxyl groups in close proximity (e.g. bacterial surface). Thus it was proposed the Sbi III-IV provided a fluid-phase transacylation target for C3 cleavage and cause non-effective activation of the alternative pathway. Since mutational study confirmed the Sbi-IV was responsible for the complement inhibitiory effect, Sbi-III was proposed to be important in consumptive complement activation. Once again, Sbi IV adopts the triple helix structure, arranged in a similar fashion as Efb-c and Ehp (Fig. 1.2). Just like Efb and Ehp, the binding of C3dg to CR2 was inhibited by Sbi-III-IV, implying that Sbi may also influence adaptive immunity . 1.4.3.4 Preventing phagocyte extravasation and chemotaxis 1.4.3.4.1 CHIPS; FLIPr and FLIPr-like CHIPS (the chemotaxis inhibitory protein of S. aureus) was identified for its ability to prevent neutrophil chemotaxis to formylated peptide and C5a. CHIPS encodes a 121-amino acids (aa) secreted protein and presents in 62% of S. aureus clinical isolates. Postma et al demonstrated that CHIPS selectively and directly bound to C5a receptor (C5aR) and formylated peptide receptor (FPR) expressed on cell surface and competed with their respective ligands for binding. Receptor activation, as measured by the Ca2+ influx and murine neutrophil migration to the injury site, was inhibited. The two receptors were shown to interact with different areas on CHIPS. The N-terminal 6 residues of CHIPS, F1 and F3 in particular, were identified as the FPR binding sites. While the C5aR-binding domain was mapped to residues 31-121, which forms a packed structure similar to the ÃŽ ² grasp domain. Arginine 44 and lysine 95 were shown to be critical for its antagonizing activity. C5aR binds CHIPS through its N-terminus residues 10-18. These residues were suggested to be either involved directly in C5a binding or were required to stabilize the interaction. Therefore, CHIPS may function by direct competing with C5a or by disrupting the formation of the stable ligand/receptor complex . Two more S. aureus proteins were found to inhibit neutrophil chemotaxis. The secreted FPR-like 1 inhibitory protein (FLIPr) and its homologue FLIPr-like bound FPR and FPR-like 1 receptor (FPRL1). The N-terminal 6 residues of both proteins were important in both interactions but the phenylalanine was not critical for FRP binding. The inhibition of FPRL-1 by both proteins occurred in the nanomolar range. FLIPr-like was shown to be a potent inhibitor for FPR with activity comparable to CHIPS. However, animal infection models with chips or flipr isogenic deletion strains has not been reported. The contribution of CHIPS in bacterial infection is yet to be determined . 1.4.3.4.2 Map Map (MHC class II analog protein a.k.a. Eap) is a multifunctional 60-70 kDa secreted protein expressed by 97% of S. aureus isolates. It is an anti-inflammatory molecule that reduces leukocyte availability and function. Map can interact with a wide range of host ligands, including Fg, Fn and ICAM-1 (intercellular adhesion molecule-1). Map largely blocked ICAM-1 mediated firm adhesion and transmigration of neutrophil. In a peritonitis mice model, intraperitoneal injection of Map or pre-treatment of mice with Map showed 50-75% inhibition of neutrophil recruitment. Neutrophil infiltration in mice infected with a map- strain was 2-3 folds higher than that seen with a map+ strain, demonstrating Map inhibits ICAM-1 mediated neutrophil migration in vivo. Interaction of Map with ICAM-1 may modify signal transduction in leukocytes. NF-ÃŽ ºB activation and tissue factor release in THP-1 cells were diminished by Map treatment. A substantial amount of IL-6 and TNF-ÃŽ ± and a smaller amount of IL- 4 were released from Map treated human CD14+ PBMC in vitro. Anti-ICAM-1 antibody blocked the action, suggesting the induction was also mediated by ICAM-1. It is not clear if cellular processes other than cytokine production are also influenced, although Maps effect on PBMCs appears to be dose dependent . In addition to the cytokine changes, T cell function was impaired by Map. Mice treated with Map showed significantly reduced T cell mediated delayed-type hypersensitivity (DTH) and T cell proliferation. Adoptive transfer of T cells from Map-treated mice to untreated recipients prevented the recipients from developing DTH when challenged with allergen. The Map

Non-steroidal Anti-inflammatory Drugs: Mechanisms of Action

Non-steroidal Anti-inflammatory Drugs: Mechanisms of Action Non-steroidal anti-inflammatory drugs are a type of drugs that can be used as pain killers. Nowadays, other pain killers such as paracetamol are more widely used, as they have fewer side effects, and cost less. However, NSAIDs are mostly used in conditions which cause inflammation. It may take from a few days to more than three weeks to show their anti-inflammatory effects. They are specifically used to treat arthritis, menstrual cramps, sports injuries, and headaches. There are different types of NSAIDs that are used in different situations. For example, Ketorolac (Toradol) is only used for short-term treatment of moderately severe acute pain that otherwise would be treated with opioids. (Ogbru, 1997). Aspirin is also a NSAID that is used long-term, at low doses, specifically to inhibit blood clot formation and prevent heart attacks and strokes in individuals at high risk for developing blood clots. The most common and undesirable side effects of NSAIDs are nausea, vomiting, diarrhoea, decreased appetite, constipation, rash, dizziness and headache. The most severe side effects are kidney failure, liver failure, ulcers and prolonged bleeding after an injury or surgery (Ogbru, 1997). Mechanisms of Action Prostaglandins are a group of lipid compounds that are produced by specific group of enzymes called cyclooxygenases from arachidonic acid (Zeilhofer, 2007), which promote vital functions in inflammation, pain, fever; support the blood clotting function of platelets; and protect the lining of the stomach from the damaging effects of acid (Ogbru, 1997) (Figure 1). Mode of action of NSAIDs is to exert anti-inflammatory, analgesic (pain relieving), and antipyretic (fever-reducing) effects through the blockade of prostaglandin synthesis via non-selective inhibition of cyclooxygenases (COX-1 and COX-2) isozymes (Chakraborti et al., 2010). Both COX-1 and COX-2 enzymes produce prostaglandins that serve inflammation, pain and fever. However, only COX-1 produces and regulates prostaglandins that protect the stomach (gastrointestinal) and support platelets (Ogbru, 1997) (Figure 2). NSAIDs reduce the concentration of prostaglandins throughout the body by blocking the COX enzymes. As a result of this, ongoing inflammation, pain and fever are decreased. For example, when concentration of prostaglandin E2 (PGE2) elevates in certain parts of the brain, body temperature increases. This increase in body temperature changes the firing rate of neurons that control thermoregulation in the hypothalamus. Aspirin which can act as an antipyretic, work by inhibiting the enzyme cyclooxygenase and reducing the levels of PGE2 within the hypothalamus of the brain. As a consequence, body temperature falls, and fever is relieved (Aronoff Neilson, 2001). It is important to understand that the pain pathway is not the same for fever and other cases like tissue injuries. In tissue injury, prostaglandins together with other agents like histamine, act on the sensory neurons present in the injured or stimulated tissue which in turn conduct the generated signal to the spinal cord. The afferent fibres (neurons) transmit the pain signal to the spinal cord. The signal is then propagated from the spinal cord to the pain centres in brain. This is carried out by synapse formation between afferent sensory neuron in the dorsal root ganglion of the spinal cord, transferring the signal up the spinothalamic tract to synapse in the thalamus. Therefore the final synapse with the primary sensory cortex fibres occurs in the thalamus (Lorne, 2010) (Figure 3 4). As a result of this, pain centres in brain will become alerted and body will feel the pain. Therefore, prostaglandin synthesis inhibition by NSAIDs will result in pain pathway blockage, hence reduc ing or killing the pain. Irrespective of the type of injured tissue (ligament, tendon or muscle), the body reacts to injury with a sequence of events that initiates with an influx of inflammatory cells and blood. Removal of debris and recruiting growth factors e.g. cytokines toward the injury site are the subsequent events that are carried out by the inflammatory cells. The same Prostaglandins that are blocked by NSAIDs are partly involved in this inflammatory stage. In a normal healing process (without application of NSAIDs), a proliferative stage consisting of a mixture of fibroblasts and inflammatory cells naturally follows the inflammatory stage. At this stage, the fibroblasts construct a new extracellular matrix and continue into the maturation stage (final stage) where functional tissue is laid down. The crucial point is that each stage of repair is a prerequisite for the subsequent stage. Hence, although blocking the inflammatory stage by NSAIDs relieves the pain, it may delay the healing of musculosk eletal injuries (Stovitz Johnsons, 2003). Side effects of NSAIDs such as ulcers and bleeding promotion are due to reduction in bodys prostaglandin level which protects the stomach and supports platelets and blood clotting. In other words, NSAIDs like aspirin, especially in high doses, act as pain killers by reducing prostaglandin concentration; however, this reduction can also raise severe unwanted effects like ulcers (Ogbru, 1997). There are various NSAIDs in terms of potency, duration of action, body elimination manner, how strongly they inhibit COX-1 and their tendency to cause ulcers or promote bleeding. The more an NSAID blocks COX-1, the greater is its tendency to cause ulcers and promote bleeding. One NSAID,  celecoxib  (Celebrex), blocks COX-2 but has little effect on COX-1, and is therefore further classified as a selective COX-2 inhibitor. Selective  COX-2 inhibitors  cause less bleeding and fewer ulcers than other NSAIDs. (Ogbru, 1997). Rofecoxib (tradename = Vioxx) In 1999, two new highly selective COX-2 inhibitors, known as coxibs (celecoxib and rofecoxib) which were claimed to have low gastrointestinal (GI) side effects were introduced which resulted in high commercial development. Rofecoxib (Vioxx) was introduced by Merck (one of the largest pharmaceutical companies) as a more effective and a safer alternative to NSAIDs for the treatment of pain associated with osteoarthritis (Krumholz et al., 2007). While found to have fulfilled these goals in part, a worrying series of events took place in the late 2004 period when rofecoxib was withdrawn worldwide from the market because of alarming cardiovascular incidents and concerns about increased risk of heart attack and stroke due to long-term, high-dosage use. Other coxibs were subsequently withdrawn on suspicion of having the same adverse effects, although to a varying degree (Rainsford, 2007). Previous to introducing the drug to the market, it were concerned that the drug might have adverse effects on the cardiovascular system by changing prostacyclin to thromboxane ratio, which have opposite effects on regulating blood flow and clotting. (Prostacyclin and thromboxane are members of the family of lipids known as eicosanoids.) (Krumholz et al., 2007) A study sponsored by Merck during 1996-1997 reported that rofecoxib decreased the concentration of prostacyclin metabolites in urine in healthy volunteers by about half. Merck officials sought to soften  the academic authors interpretation that COX-2 inhibition within the vascular endothelium may increase the propensity for thrombus formation, the basis of what became  known as the FitzGerald hypothesis. The academic authors changed  the manuscript at Mercks request-for example, they changed  systemic biosynthesis of prostacyclin was decreased by  [rofecoxib] to Cox-2 may play a role in the systematic biosynthesis  of prostacyclin. (Krumholz et al., 2007). However, despite knowing that rofecoxib may elevate thrombus formation, none of the studies that constituted Mercks new drug application to the Food and Drug Administration (FDA) in 1998 were designed to examine cardiovascular risk. The studies were all generally small, had short treatment periods, enrolled patients at low risk of cardiovascular disease, and did not have a standardised procedure to collect cardiovascular results (Krumholz et al., 2007). In 1999, the largest study on rofecoxib, the vioxx gastrointestinal outcomes research (VIGOR), took place by Merck. The purpose of the study was to show that the drug would have fewer GI side effects than naproxen (NSAID) for the treatment of rheumatoid arthritis. The study took place without a standard procedure for collecting information on cardiovascular events. Finally, the study showed that rofecoxib was not more effective in terms of mitigating symptoms of arthritis but halved the risk of GI events. However, the study showed that there was also evidence of an increased risk of myocardial infarction. Therefore, the first suspicion about the metabolite meanings i.e. urine prostacyclin data was right. Nevertheless, Merck decided to propose a naproxen assumption, implying that rofecoxib had not been harmful but that naproxen had been protective, despite having no evidence that naproxen had a protective effect on cardiovascular system (Krumholz et al., 2007). Finally, after wide usage of Vioxx in clinical centres around the world for around 5 years, due to an increase in serious cardiovascular events, the company voluntarily withdrew Vioxx from the market, in 2004. Currently, a lot of studies are taking place to discover why cardiovascular failures took place with coxibs, to identify safer coxibs, and to clarify the roles of COX-2 and COX-1 in cardiovascular diseases and stroke in order to develop newer agents to control these conditions (Rainsford, 2007). Overall, in order to improve the care of patients and gain their trust back, putting patients interests first is necessary. A renewed commitment and re-establishing collaborations between industry, academics, journals and practising doctors are the only way to extract something positive from this unfortunate event.