Globalization Positive Effects

University American College Skopje School of Business Administration Final paper Spring Semester 2011 International Management & Globalisation Instructor:Student: Professor Dimitrios E. Akrivoulis Vlatko Bogoevski ID: 9243 Skopje, April, 2011 Table of content: Globalization Impact of the globalization Positive effects of the globalization †¢ Increased Competition †¢ Employment †¢ Investment and Capital Flows †¢ Foreign Trade †¢ Spread of Technical Know-How †¢ Spread of Culture †¢ Spread of Education †¢ Legal and Ethical Effects Negative impact of the globalization †¢ Employment issues Safety and security concerns †¢ Environmental issues †¢ Other negative effects What is the influence of the globalization process in India Globalization effect to the Indian women What are the main players in the process of Globalizations †¢ Transnational Corporations †¢ Investors †¢ World Trade Organization †¢ World Bank and IMF †¢ U. S. Treasury Department †¢ NGO’s Abstract: The purpose of this paper is to introduce, discuss, and analyze the topic of Globalization. Specifically it will discuss the positive and negative effects of the Globalizations, and how it reflected to the Indian market.In addition, it will provide information of the main players in the globalization process and which organizations played the most important rule in setting up the international law and regulations. Summary: It is clear that globalization is something more than a purely economic phenomenon manifesting itself on a global scale. Based on my broader research of the topic of globalization and its effects, we may conclude that the process has had many positive and negative aspects. Some countries gained more benefits than others; some people lost their jobs while some of them get employment using the benefits of the globalization.Taking the positive side in the process, I believe that international organizat ions and governments have to support the phenomenon of globalization by implementing fair rules and regulations equal for all players and countries. International organization like WTO, World Bank, IMF have to foreseen the countries especially developing countries to change the criteria of attracting foreign companies in which the resources, safety and country stability will be the main criteria of attracting foreign capital, rather than exploitation labor force or neglecting the main safety and environmental standards.By creating a fair competition the trend of multi nationals companies will slow down and will provide room for development and maintain of small and medium companies. Strict law and regulations has to be foreseen from the international organizations to the governments and main players (multinational companies) in the process of globalization in which they will monitor the effects and take the right actions that will boost only the positive and beneficial aspects. Glob alization People in the world are much more connected than ever before.Goods and services produced in Asia or Africa short after are available on the other continents in the world. Travelers moving in other countries more frequent. International communication based on last technology achievements, (the internet) make people to communicate in much easier way than ever before. Information, data, and money flow are trade all around the world quickly than ever. This phenomenon has been named as Globalization. In the modern world globalizations has been identified as system of communications and relations among the countries that will help to develop the global economy and people living standard.It mostly refers to the integration of trade and industry, political and cultural exchanges all over the world. [1] Joseph Stiglitz, an economist and winner of the Nobel Prize defines globalization as the closer integration of the countries and peoples of the world †¦ brought about by the en ormous reduction of costs of transportation and communication, and the breaking down of artificial barriers to the flows of goods, services, capital, knowledge, and people across borders. [2] Impact of the globalizationSome argue that globalization is a positive development as it will help to develop new industries and will create more jobs in developing countries, while other says that the globalization is negative. They believe that it may force poorer countries of the world to do whatever the big developed countries tell them to do. Another viewpoint is that developed countries, like USA, Canada, are the ones who may lose out because they are involved in outsourcing many of the manufacturing jobs that used to be done by their own citizens.Positive effects of the globalization: The positive effects are numerous and extremely beneficial for everyone in all countries. The following effects have been identified as the major benefits of the Globalization: Increased Competition It†™s more than obvious if the market is bigger and more companies could offer the products at the same market and under same conditions the final consumers would feel the benefic in terms of financial and quality. Customer service approaches to production have led to improved quality of products and services.As the domestic companies have to fight out foreign competition, they are compelled to raise their standards and customer satisfaction levels in order to survive in the market. Employment Many companies like NIKE, Mercedes, Procter&Gamble, have transferred the production into developing countries having the opportunity to use the benefits of it, like reducing the unemployment rate, higher government revenue expectation due to different taxes etc. However, the employment benefit of the globalization may have negative effect.Due to global nature of the businesses, people of developing countries can obtain employment opportunities, but the developed countries have lost jobs on acco unt of this movement of jobs to the developing world. Investment and Capital Flows One of the most positive impacts of globalization in China is the flow of foreign capital. Many companies have directly invested in China by starting the production factories there. Chinese companies which have been performing well, both in China and abroad, will attract a lot of foreign investment, and pushes up the reserve of foreign exchange available in China.This is also one of the positive effects of globalization in US and other developed countries as developing countries give them a good investment proposition. Foreign Trade Foreign trade has had positive impact records in the history. Globalization process through different organization like World Trade Organization, IMF and others have been established with a view to control and regulate the trade activities of the countries. [3] Spread of Technical Know-How It is generally assumed that all the innovations happen in the developed countries.D ue to globalization the know-how comes into developing countries that help them to use the benefits of it and speed up the developing process. Without globalization the knowledge of new inventions, medicines would remain in the countries that came up, and no one else would benefit. But due to improved political ties, there is a flow of information both ways. Spread of technical know how may be counted as one of the most positive aspect of the globalization. [4] Spread of Culture This effect of globalization has many positive impacts but also we may find it as reason of intolerance between different nationalities that leads to wars.Societies have become larger as they have welcomed people of other civilizations and backgrounds and created a whole new culture of their own. Cooking styles, languages and customs have spread all due to globalization. The same can be said about movies, musical styles and other art forms. They too have moved from one country to another, leaving an impressi on on a culture which has adopted them. Spread of Education One of the most powerful positive effects of globalization to the people is the spread of education. People from different continents may study abroad and gaining the positive experience may not find in their own country.A good example of that is how the American managers went to Japan to learn the best practices in the field of mass production and incorporated that knowledge in their own production units. Legal and Ethical Effects Gone are the days where the limited jurisdiction became a barrier in the prosecution of criminals. These days due to international courts of justice, these criminals can no longer seek protection in a foreign country. Due to globalization, there is also an understanding between the security agencies and the police of two or more different countries who will come together to curb  global terrorism.This is undoubtedly one of the greatest positive effects of globalization on society. [5] Negative impact of the globalization Globalization has the negative side as well. Opponents of the globalization point out to the following negative effects: Employment issues Many companies have transferred the manufacturing work in developing countries like China where the cost of the production goods are lower. That means fewer jobs for the people in developed countries. Programmers, accountant and others in developed countries lost their job due to outsourcing to cheaper location like Pakistan, India. Etc.In additional, globalization has led to exploitation of labor. P Prisoners and child workers are used to work in inhumane conditions while safety standards are ignored to produce cheap goods. Job insecurity seems to be real problem of globalization. While in the past people had stable and permanent jobs, today they live in constant dread of losing their jobs to competition. Increased job competition has led to salary reduction and lower standards of living. Safety and security concerns Advanced technology does not mean that always will be used in a proper way, like to improve the people life or to benefit the global economy.Terrorists use the internet to communicate between themselves and also they have access to sophisticated weapons that increase their ability to inflict damages. This is undoubtedly the negative effects of the globalization. [6] Environmental issues Many companies in the developing countries have set up the industries causing pollution due to the poor environmental regulation. Other negative effects: †¢ Bad aspects of foreign cultures are affecting the local cultures through TV and the Internet. †¢ Enemy nations and organization can spread propaganda through the Internet.The domino effect in the Egypt and Libya come as the result of fast and easy channels of transferring information. †¢ Deadly diseases are being spread by travelers to the remotest corners of the globe. †¢ The increase in prices has reduced the government†™s ability to sustain social welfare schemes in developed countries. †¢ Multinational companies and corporations which were previously restricted to commercial activities are increasingly influencing political decisions. [7] What is the influence of the globalization process in IndiaIndia opened up the economy for foreign investors in the early nineties. The new government has implemented law, regulations, and globalization strategy that will be in favor of international businesses and radically pushed forward market oriented economy. The government of India made changes in its economic policy in 1991 by which it allowed direct foreign investments in the country. As a result of this, globalization of the Indian Industry took place on a major scale. Liberalization that was established in the 1990’s included the following major changes: Modifying of the industrial licensing regime, †¢ Reduction in the number of areas reserved for the public sector, †¢ Amendment of the monopolies and the restrictive trade practices, †¢ Start of the privatization programme, †¢ Reduction in tariff rates and change over to market determined exchange rates. [8] Over the years the liberalization of the Indian market become reality, more and more sectors opened up for foreign direct investments facilitating the entry of industries like steel, pharmaceutical, petroleum, chemical, textile, cement, retail and etc.One of the great changes, the sharply reduction of the tariffs rates contributed to speed up the process of foreign investment. â€Å"The Indian tariff rates reduced from average of 72. 5% in 1991-92 to 24. 6 in 1996-97. Though tariff rates went up slowly in the late nineties it touched 35. 1% in 2001-02. India is committed to reduced tariff rates. Peak tariff rates are to be reduced to be reduced to the minimum with a peak rate of 20%, in another 2 years most non-tariff barriers have been dismantled by March 2002, including almost all quantitat ive restrictions. [9] One of the major impacts of the globalization in Indian industry is that many international companies have decided to invest there particularly in the pharmaceutical, petroleum, and manufacturing industries. It helped Indian economy to develop significantly. Those investments has reduced the unemployment rate in country and brought highly advanced technology that helped to make the Indian Industry more technologically advanced. The various negative effects of Globalization on Indian Industry are that it increased competition between the foreign and domestic companies.Goods produced by the foreign companies were cheaper and better to the one produced by the domestic companies. It reduced the profit of the domestic companies and many people lost the jobs. This happened mainly in the pharmaceutical, manufacturing, chemical, and steel industries. The negative effects of Globalization on Indian Industry are that with the coming of technology the number of labor requ ired decreased and this resulted with higher unemployment rate. [10] Globalization effect to the Indian women: Globalization has had negative implications for Indian women.According to estimates from World Development Indicators, â€Å"Women work two-thirds of the world’s working hours, produce half of the world’s food, but earn only ten percent of the world’s income, and own less than one percent of the world’s property. †[11] In India most of the women work two full time jobs. One in a factory where they are paid almost nothing, the  other is in home where they are paid nothing. One example of women’s labor being exploited would be the Noida Export Processing Zone, which is 24 km from  New Delhi. These â€Å"zones† prefer to hire women because they are more docile and more productive in men.In short they are easier to control and less likely to retaliate against less than ideal working conditions, which are exactly what thousand s of women encounter 12 hours a day. The zone is dangerous, hot, and unsanitary. Unnecessary body searches are routine. There are no maternity benefits and minimum wage is never enforced. Women who become pregnant or marry are immediately fired. Overtime is compulsory but women are paid lower rates than men. In order to avoid being fired, women turn to unsafe abortions performed by unqualified â€Å"doctors. In the zone â€Å"respiratory problems, pelvic inflammatory disease, and sever cases of dehydration and anemia are common. †[12] What are the main players in the process of Globalizations Transnational Corporations: Large corporations (such as Nike, Hanes, Dole, Exxon, etc. ) that operate mostly in developing countries, are not regulated by any international body and because making a profit is their main responsibility, they often move factories in nations that offer the lowest wages, environmental standards, taxes, etc. with aim to maximize the profit and lower the prod uction costs.Of the world’s primary economic financial powers (with the largest revenue), 49 are countries— and 51 are corporations. [13] Investors: Investment firms, banks, mutual funds and hedge funds, etc. , who â€Å"move† money around constantly, buying and selling internationally. World Trade Organization: â€Å"The General Agreement on Tariffs and Trade and international trade agreement which developed at the Bretton Woods Conference. This conference also created WTO the United Nations, the World Bank and the International Monetary Fund.The WTO develops and enforces trade rules for all member nations; for example it can decide that certain country’s environmental standards are unfair barriers to trade. World Bank and IMF: The World Bank and IMF make loans for development purposes (roads, power plants, etc. ) to developing countries to move people out of poverty and into self-sufficiency. When poor countries fall behind in loan payments (they canno t seek bankruptcy protection like corporations such as Enron can), the Bank makes additional loans that dictate the poor country’s economic system so it can pay back the growing interest.These structural adjustment policies (SAPs) have meant countries in Africa, for example, have had to cut back funding for health care, education, and social services. People in these counties must now grow food for export to pay off loans rather than for feeding their own people. U. S. Treasury Department: U. S. Treasury department controls 17% of the World Bank and IMF decision-making power by giving it a larger share of power than any other country in decisions. It also plays a dominant role in the WTO. Many of its decisions in these bodies are shaped by the U. S.Treasury Department which handles financial and currency matters for U. S. Government. NGO’s: Non-governmental organizations are a wide range of non-profit groups representing different communities and segments of civil soci ety. Such groups are increasingly working together through growing networks to bring positive change and economic justice to people in poverty and without power. †[14] List of references: http://global_india1. tripod. com/negative. htm http://www. scribd. com/doc/49266417/Effects-of-Globalization-on-Indian-Industry http://www. buzzle. com/articles/negative-effects-of-globalization. tml http://iecblogs. org/informational/globlisation-its-impact-on-india http://usforeignpolicy. about. com/od/trade/a/whatisgz. htm http://mindtools. net/GlobCourse/gdef. shtml http://ezinearticles. com/? The-Positive-Effects-of-Globalization&id=1126427 http://www. buzzle. com/articles/negative-effects-of-globalization. html http://iecblogs. org/informational/globlisation-its-impact-on-india Business Organisation And Management (For Delhi University B. Com Hons. Course http://www. scribd. com/doc/49266417/Effects-of-Globalization-on-Indian-Industry by Phillip Tomlinson; http://www. simulconference. om/clients/sowf/dispatches/dispatch22. html http://www. ramveena. com/p/ramveena-india-is-one-of-few-countries. html http://juan-globalization. blogspot. com/ http://members. iimetro. com. au/~hubbca/globalisation. htm http://en. wikipedia. org/wiki/World_Trade_Organization http://riskreport. weforum. org/ Words: 2779 ———————– [1] http://usforeignpolicy. about. com/od/trade/a/whatisgz. htm [2] http://mindtools. net/GlobCourse/gdef. shtml [3] http://en. wikipedia. org/wiki/World_Trade_Organization [4] http://members. iimetro. com. au/~hubbca/globalisation. htm [5] http://ezinearticles. com/?The-Positive-Effects-of-Globalization&id=1126427 [6] http://riskreport. weforum. org/ [7] http://www. buzzle. com/articles/negative-effects-of-globalization. html [8] http://iecblogs. org/informational/globlisation-its-impact-on-india [9] Business Organisation And Management (For Delhi University B. Com Hons. Course [10] http://www. scribd. c om/doc/49266417/Effects-of-Globalization-on-Indian-Industry [11] by Phillip Tomlinson; http://www. simulconference. com/clients/sowf/dispatches/dispatch22. html [12] http://www. ramveena. com/p/ramveena-india-is-one-of-few-countries. html [13] http://juan-globalization. blogspot. com/ [14]

Ansoff’s Matrix Explanation Essay

Using the same product in the same market, however altering the looks or the style of the product to make is look new to encourage higher sales. E.g. Coca-Cola using different styles of coke and using different advertising campaigns to sell the same coke product. Product development When a new product is used in the same market. For example if coke sold juice, it would still be in the same drinks market however it would be a different product. New market Market development Selling the same product to a new market. It has a higher risk because it is a different set of customers. An example of this is Tesco’s expansion into petrol sales. Diversification A new product to be sold in a completely new market. This has a higher risk because it is a completely new idea and may not catch-up quickly which may lead to the company making a loss. A good example of the unrelated diversification is Richard Branson. He took advantage of the virgin brand and diversified into various fields such as entertainment, air and rail travel foods etc. Ansoff’s Matrix Main Definition: â€Å"The Ansoff Matrix is a strategic planning tool that provides a framework to help executives, senior managers and marketers devise strategies for future growth. It was created by Russian American, applied mathematician and business manager, Igor Ansoff† The Ansoff Growth matrix is a marketing planning tool that helps a business determine its product and market growth strategy

Chipotle Grill Case Study Essay

What does a SWOT analysis reveal about the attractiveness of Chipotle Mexican Grill’s situation and future prospects? There are a lot of things about Chipotle that have kept them successful in previous years. Opportunities and strengths depict that presently the company has a strong and positive image in its established markets which is mainly in the U.S., U.K. and Canada. Strong brand recognition drives the company. Customer loyalty allows a long-term positive impact to Chipotle, which enhances company value. Targeting a group who is health conscious, environment friendly and loves Mexican fast food keeps Chipotle on the forefront of success. Chipotle has an extensive line of nutritionally balanced menu items derived from both organic and naturally raised ingredients. This idea led to the concept of â€Å"Food with Integrity† (Gamble, Thompson, Jr., & Peteraf, 2015, p. 303). Chipotle’s reputation encases ethical and charitable standards along with healthy choice s for the consumer. Chipotle is â€Å"company-owned†, not a franchise so maintaining integrity is easier. Customers may choose to dine-in, take-out, and even order online to pick-up in the restaurant. These options have strengthened the company by offering convenience and availability to the customer. The brand also has a bright future in the untapped regions and with ample scope of introducing new food items in its menu. The creator of Chipotle came up with five core elements in which to base the strategy of the establishment: †¢Serving a focused menu †¢High quality, reasonably priced, convenient menu items †¢Operational efficiency †¢Friendly staff †¢Awareness and respect for the environment Chipotle’s Strategy Chipotle’s strategy is one of differentiation. Specific types of food that can be produced through local, environmentally conscious, farmers at an affordable price point is a primary goal. Offering natural food raised from local, organic vendors that customers respect yet still at an affordable, fast food price, creates a stand apart from the competition. Another way Chipotle differentiates from the competition is through human resource practices. People from all ethnicities are brought together to bridge cultural and linguistic gaps between both employees and customers. Chipotle  has a team dedicated to empowering, educating, and training employees to increase internal promotions, cultural sensitivity, and communication skills. The company prides itself on hiring from within and providing employees with opportunities to grow. The key element of Chipotle’s strategy is â€Å"Food with integrity† (Gamble, Thompson, Jr., & Peteraf, 2015, p. 303). Sourcing supplies from natural, organic, and sustainable, and environmentally friendly growers/producers is an essential strategy is maintaining market standing. Not many restaurant chains, if any, can say they are consistent in this practice, which makes Chipotle rise above the rest. More and more people are making the choice to choose to eat healthier which makes Chipotle an excellent choice and places them in a strategic place in the fast food industry. With more healthy choices than other fast food establishments such as Taco Bell, consumers are more likely to choose Chipotle. Another key element to the strategic plan is operating efficiently in an aesthetically pleasing environment. Even though it is fast food, Chipotle doesn’t offer a fast food setting when dining in. With a modern theme of bamboo or stained concrete flooring, pendulum lighting, and outdoor patios where available, Chipotle has reduced the cost of building and maintaining new establishments but still managed to keep the aesthetically pleasing, not-so-fast food ambiance. How does Chipotle Mexican Grill’s competitive strength compare against that of Taco Bell, Qdoba Mexican Grill, and Moe’s Southwest Grill? Chipotle is not as visibly prominent here in the South as it is in other states compared to Qdoba Mexican Grill, but more so than Moe’s Southwestern Grill. In recent months, Chipotle expanded into the Memphis area in the Poplar/I-240 area in a new shopping center near Target and Best Buy, surrounded by a variety of other restaurants and businesses. Chipotle, Qdoba, and Moe’s all strive for market presence by positioning themselves in areas convenient to shopping centers, in strip malls, and near business centers. They are equal in the â€Å"Employment Practices† category as all strive to promote from within and offer strict training and development programs focusing on expanded knowledge through certification processes. The differences that stand out, allowing Chipotle to excel strategically are in Customer Service, Menu Selection, and Quality. Chipotle prides itself on  having a genuine concern for the patron by hiring individuals from all walks of life and et hnicities. Whatever language a customer speaks, or ethnic background they are from, there is probably a Chipotle team member who can connect with them to walk them through the dining experience. Qdoba Mexican Grill and Moe’s Southwestern Grill have attempted to connect through customer service and experience but are not making as strong of a head wave as is Chipotle. There is truly a unique dining experience to talk about at Chipotle that draws patrons back for more. The menu selection at Chipotle consists of the highest quality natural and organic selections from local growers and farmers. Fresh sweet corn, organically grown cilantro, organic chili and pablano peppers, grass-fed beef, and free-range chicken are just a sampling of the examples of quality raw ingredients used by Chipotle Mexican Grill. Through high measurements of sustainability in sourcing of these raw ingredients to construction of each restaurant, Chipotle has easily earned a 10 in this category regardless of the price point associated with the final product. The quality of the food served at Chipotle is always above par. The cooking methods allow flavorful, robust, creations to be made in a short amount of time without damaging the integrity of the raw materials. Through consistent accuracy and quality measures, aesthetically pleasing plating is also displayed with each order, down to the containers in which to-go orders are placed. What does an analysis of the data in case Exhibit 1 reveal about Chipotle’s financial and operating performance? Financial201220112010 Asset Turnover1.6371.5921.637 Inventory Turnover179.4188.6189.7 Liquidity Quick Ratio1.8162.6021.873 Current Ratio2.9253.1833.301 Investments/Shareholders Earnings Per Share8.846.885.76 Profitability Gross Profit Margin27.1%26.0%26.7% Operating Profit Margin16.7%15.4%15.7% Net Profit Margin10.2%9.5%9.7% Return on Capital22.3%20.6%22.1% The inventory turnover ratio shows that they are able to turn over their inventory very quickly. The asset turnover ratio shows that they are able to convert their assets into sales. Their liquidity ratios are good because above 1 is good and above 2 is even better. Their Earnings Per Share show that the company is trending to increase profitability and their shareholders should see an increase in value. The profitability margins have been able to grow over the past years. The financial well being of Chipotle is stable and improving. Unless something drastic occurs, anticipating the rise in revenue and value years from now, a positive future will be in store for Chipotle. Key Strategic Issues Chipotle has many strengths that make it an attractive company but they also have some weaknesses. In recent years, competitors have started offering healthier menu options at lower price points. Taco Bell’s cantina menu is much like the Chipotle brand in which it offers more of a lighter southwestern flare than traditional Mexican dishes. The menu pricing at Chipotle is higher but is due much in part by the use of organic and natural selections, some of which are difficult to obtain in winter months. With difficult growing seasons across the United States, Chipotle may have to choose to change their menu in winter months. With limited menu items and ingredients that have price volatility it may not be a smooth establishment in new states and countries. Competitors are the largest threat to Chipotle. As previously stated, other fast food restaurants are adding lighter fare to their menu at a lower price that Chipotle. With the continued high costs of natural and organic menu o ptions, menu prices may have to change to keep margins stable. Another impact to the bottom line could be rising healthcare costs that may require a shift in employment for many restaurants. Chipotle has multiple opportunities to expand into other states as well as internationally. With locations in the District of Columbia, Canada, the United Kingdom, and France, Chipotle managers should be well versed in the workings of International business management. With expansion into other countries and the continued use of locally grown and raised staples, Chipotle would stand to make substantial profits in countries like  China and India. Adding ingredients indigenous to each local area would promote the brand customers have grown to admire. As restaurants like Taco Bell and On the Border sell their products in grocery stores, Chipotle could follow suite and add profit to their bottom line. Restaurants like Swanky’s Taco Shop have alcohol and beer on the menu, now so does Chipotle in some states. Continuing this growth in other states would be a plus for growth as well.

Critique and conclusion of context & rationale paper Essay

Critique and conclusion of context & rationale paper - Essay Example However, that alone is not the sole purpose of rainwater harvesting. Places which receive tremendous amount of rainfall every year have as much a reason for harvesting water as those living in the Sub-Saharan deserts. It is imperative to keep in mind that effective utilisation of water is the key to reduce droughts and floods at the same time. What comes to the rescue is effective design of methods that cater to the immediate requirement of a particular region. One of the best examples is the use of LifeStraw as a water purification method. â€Å"Lifestraw was created by Danish inventor Torben Vestergaard Feandsen. The product could be a lifesaver† (Fridell 58). It is nothing but a tube that one can use to suck water. The water gets purified when it passes through the levels of filtration. This kind of wonderful design is so portable and convenient to use that people do not actually have to set up any complex infrastructure for the same. Thomas Dickson in his book ‘Dansk Design’ has described the implications of LifeStraw on the formidable task of preventing water borne diseases. He says that this product helps in preventing diseases that include typhoid and cholera which result in the deaths of millions every year. Dickson has also presented an interesting point about the lifespan of the product. â€Å"The lifespan of one straw is about 700 litres of water, so with a consumption of two litres a day, the straw can last about a year† (Dickson 550). However, things change when there is a polar shift in the availability of water. In areas that receive very heavy rainfall throughout the year, a large amount of water is directly Rainwater 4 drained without even considering a reuse plan. Considering the damaging impact that a country can face due to a shortage of water, it becomes imperative to understand the importance of saving every drop of water that can be saved. And in doing so, it is an interesting fact to notice the diversities in d ifferent regions. If some places need to conserve water due to less rainfall, some have to do that to prevent water loss. Over the years, several designs have evolved which are tailor made for the particular environment. ‘Raincatch’ is one such example that serves as an easy water harvesting method. It resembles a raincoat with an enhanced collar that serves the purpose of catchment in a rainwater harvesting system. With the help of an inbuilt filtration system, water gets accumulated at the bottom part of the coat through which it can be sucked using attached tubes. This design is the result of an innovative thinking of two Copenhagen Institute of Interaction Design students. What is wonderful about this design is the practical approach coupled with the intention of harvesting rainwater. ‘Green Trace’ is another such example that proves how water can be saved without so much of an effort. It is a design consisting of a rectangular mesh that houses a non-wo ven fabric inside it. This fabric has water absorbing capabilities and it holds the seeds in between its sewing patterns. This entire mesh acts as an umbrella stand which captures all the water from a wet umbrella to be passed onto the seeds. The ultimate result is a gradual growth of plants that form a beautiful design pattern. This design, though very simple, is pretty helpful in optimising the use of water that otherwise may be wasted. It

International Business Law Essay Example | Topics and Well Written Essays - 750 words

International Business Law - Essay Example India has no data protection law and therefore, there is no law regulating the protection of personal data of staff and employees that are kept in the databases of companies. What India has is the Information Technology 2000 (IT Act 2000) which prohibits the disclosure of data by a person who has secured access to it without the consent of the person whose personal data is being disclosed. The foregoing piece of legislation has therefore, a very narrow application and does not really protect information in company databases from persons who have no secured access to it (Spedding & Rose 307). In a contract where two parties come from different countries, two sets of law are naturally involved – that of the host country and that of the country of the outsourcing party. In such instances, the parties to the contract must expressly signify in the contract which law must govern the parties’ contractual relationship. Under the Indian judicial system, the choice of law of the parties called â€Å"the proper law of the contract† is respected and upheld by the Indian courts. Thus, if StoneTechnical enters into an agreement with an Indian counterpart for the outsourcing venture, the parties must agree by themselves which law should govern their contractual obligations and in case of a dispute under which law should the rights of the parties be determined. In addition, foreign judgments are enforceable in India so long as a reciprocal arrangement exists between India and the country of the outsourcing or FDI country as can be gleaned from the provisions of the Indian Civil Procedure Code. In the absence of such an arrangement, enforcement of such judgment can be had through the filing of an action for its enforcement (Sople 2009 p. 96). Aside from the foregoing, particular legal issues for outsourcing that are not potentially advantageous to StoneTechnical are the following: absence of at-will employment; statutory protection in employment to a class of

Union Management Essay Example | Topics and Well Written Essays - 500 words

Union Management - Essay Example This bad news has serious implications for most unions, putting them in a position of hard choices. On one hand, union leaders need to look after members’ welfare but on the other hand, they have to face some harsh realities. The truth of the matter is that state government coffers are facing a â€Å"fiscal emergency† as what Gov. Linda Lingle said and everyone must put their share of carrying the burden equally to keep things afloat. The government of Hawai’i had laid off some 900 to 1,100 government workers earlier in November and more lay-offs might be forthcoming, she had warned. In the end, everybody got what they wanted out of the deal which shows everyone concerned was willing to compromise and sacrifice. The current recession had highlighted the need for some concessions from the union, in particular work rules concerning compensation. State workers had overwhelmingly approved to take 42 furlough days, to be distributed into 18 days this fiscal year, 12 next year and another 12 for year 2011 (Sample in â€Å"Hawaii’s largest†¦Ã¢â‚¬ ). Union leaders had to face the reality of the situation and taking furlough is better than private-sector employees who took a pay cut and are working still the same hours for less pay as what Paul Brewbaker said. In another article on the same issue regarding union acceptance of the new contract, the Honolulu Advertiser mentioned that six of the seven bargaining units of Hawaii’s biggest public-sector union had ratified the new contract. Some 60% to 95% of the members had voted in support of the furlough days, roughly the equivalent to an 8% pay cut. For some of the union members, this concession may represent or symbolize the futility of being members. This is because the union had failed to protect their compensation benefits by eventually agreeing to furloughs although this is also dictated by the harsh reality of budget shortfalls. The new

Are some cultures inherently incompatible to democracy Essay

Are some cultures inherently incompatible to democracy - Essay Example However, there was a substantial drawback after Mussolini took power in Italy, and this led to reversal of gains made towards democracy. The number of democratic states reduced significantly in the world to 12 (Huntington, 1993). This was revived after allies won the World War II. This led to a second wave of democratization with 36 countries being governed democratically (Huntington, 1993). Likewise, there was a reverse wave, and the number of democracies came back to 30 (Huntington, 1993). Currently, the third wave is in operation. There are crucial factors that have contributed to the occurrence and timing of third wave move to democracy. Firstly, it is caused by the deepening legitimacy problem of authoritarian regimes in a world where democratic principles are widely accepted. Many people depended on the success of such regimes, but they have been recently faced by the inability to achieve and present economic support. Secondly, the economic success of the 1960 prompted the deve lopment of urban middle class in the majority of the countries. Thirdly, there was a modification of catholic ideologies from the maintenance of the status quo and condemnation of authoritarianism (Huntington, 1993). Fourth, there was external pressure mainly from European Community, the United States, and the Soviet Union (Owen 2002). Lastly, protest has played a key role for subsequent efforts at democratization (Ranker, L. et al. 2007). T

Sociopolitical Paper Essay Example | Topics and Well Written Essays - 750 words

Sociopolitical Paper - Essay Example vel will require to use a lot of time and resources in studying the pros and cons of the car and even more time in changing the existing road safety laws and having to formulate new ones on manufacturing, production as well as distribution. This will lead to political implications both negative and positive. The automotive industry owners will also need to get new manufacturing equipment, seek scientists and software technocrats to install the technology or use billions in purchasing the technology from Google with the returns not being felt for several more years. The first users have to incur the high cost of production through the high price of the vehicles. The impacts are acceptable. The future stakeholders are the consumers and the automotive industries that have to bear and meet the high costs of production as well as the laws changing. However, even though the initial costs may be high, the returns in the long run will be worth it with the numerous benefits these cars are promising to bring to the human generation. The government is bound to adopt the technology because in the long it will save lives and billions of dollars in road repairs and other infrastructure that are constantly damaged by road accidents, it will save on money used when drivers are arrested and charged for traffic violation among offences in relation to cars and roads. The consumers will adopt as it will save on insurance money, expenses of car repair and traffic violation as well as letting people text while still driving. When people adopt the technology and view its advantages, the other stakeholders will benefit in increased profit through mass production due to high demand. The engineers are concerned with making the car as safe as possible as their main aim is to reduce the human loss and health problem brought about by accidents. The engineers are therefore concerned with adding as many safety features as possible while at the same time ensuring the cost will not be too much

Tort review Case Study Example | Topics and Well Written Essays - 250 words

Tort review - Case Study Example Koz negligence, the prevailing comparative negligence guidelines and concept of swimmers’ legally supported to claim damages since their proportion of contribution was less than 50% 1. Under The New York modified comparative negligence rule, an injured party may recover damages only if he/she is less than 50% at fault for the injury or damages. However, the recovered amount may be reduced in proportion to the degree that the injured party was at fault. For instance, if the Peter Koz is determined to be 80% at fault and the group of swimmers is determined to be 20% at fault, the swimmers can collect for the damages because they were less than 50% at fault. However, Peter Koz insurance company might only offer to pay for 80% of your damages2. The injured party had upper hand in negotiating with the insurance company and a settlement was reached to compensate them. If the settlement could not be reached, the courts could make the final determination of comparative negligence4. The swimmers were entitled to damages as evidence indicated that there contribution to the case was 25% which is less than the 50% bar rule. Peter Koz will not prevail because his contribution is above 50% and will compensate the swimmers the damages as estimated at

Literature Review of The Use of Shame With Sexual Offences Essay

Literature Review of The Use of Shame With Sexual Offences - Essay Example Although Anne has taken an obvious standpoint in the beginning but she has presented the opposing arguments quite often in the article. The article is grounded into strong ethical boundaries and Anne has presented any personal details or hints. Public protection is the essence of any legislation either it is concerned with the pre-crime evasive measures or post-crime reclamation. The author has taken up a particular aspect of restorative justice, defined to be â€Å"a way of dealing with criminal offences by involving the offender, the victim, and possible community representatives in an informal negotiating process which results in the offender's undertaking some 'reparative' task.† (Hirsch et al. 2003). Anne give the brief overview of restorative justice and challenges it was facing. There critics of the restorative justice were asking for inflicting penalizations and penalties for the committers of sexual harassment and sexual offenders. They hold the point that this restor ative justice does not have much to tackle the culprit and offers no good to society in the long run. Deflem has observed this in his article, â€Å"policies designed to treat and rehabilitate offenders had an unacceptably low success rate – especially when evaluated in the light of the very science which produced those policies – the discretion given to judges to fit sentences to the offender and not exclusively the offense seemed misplaced.†(Deflem, 2006). However, Anne defended his stance for use of shame as an instrument for restorative justice and criticized the current ‘what works’ approach of criminal justice policy and pointed out the lack of focus in legislation and implementation on sexual offences. Anne categorically claims that â€Å"the traditional form of retributive justice does not seem to be working.† It is not only Anne but a number of other experts have already advocated in favor of restorative justice and allied tools for ensured and improved effects and outcomes from it. The relationship between society and the offender’s infliction is often overlooked by the theorists as Durkheim has argued, â€Å"the function of punishment has less to do with the offender and more to do with a collective reaction of the community to the violation of its norms and an effort to re-establish solidarity around those norms.† (Deflem, 2006). Sexual assault against children is considered to be the most offensive and heinous crime and the retributive justice despite sentencing the offender can not integrate the offender with the community which increases the chances of a second attempt by the offender. This disintegration of the offender, according to Anne is required to be change into integration with the community through restorative justice. Although it might be referred as a ‘paradigm shift’ but it has to be case if reintegration is a declared ultimate objective of the justice system. The re storative system has its own advantages that cannot be overlooked, Carrabine has argued for the same, â€Å"the use of integrative shaming techniques, mediation and reparation aim to provide an alternative and more appropriate way of resolving disputes, confronting offenders with their wrong doing and empowering the victim.† (Carrabine et al., 2009, p.174.). Anne has righteously pointed out the role of media in the success of the restorative justice and has not been helping the cause by calling it a ‘

Mind-Body Problem Essay Example | Topics and Well Written Essays - 750 words - 2

Mind-Body Problem - Essay Example The five theories include behaviorism, dualism, reductionism, functionalism, and eliminative materialism and each of them has its own tenet in explaining the behavior of a person in a certain context (Turner 4-6). According to dualism perspective of looking at human life, there are different sides of life that conflict or complement each other in the process of an individual acting in a context. For example, according to the theory, one person behaves in a certain way because of the moral dualism that exists between the people and which explains that there are two sides of morality. This means that a person’s actions can be either towards morality or against it, which is shaped by the various ways of defining morality from different contexts and societies or societal description of it (Turner 39-41). Behaviorism is a theory that explains the actions of an individual from the context of the past behavioral actions to predict because the theory argues on the bases of human exper ience in society. This theory argues that what is manifested physically by a person can be used to explain the differences that are in the mind of the individual and people can use clear analysis of behaviors to give explanations that are relevant to predicting their behavior. This means that according to behaviorists, the behavior of a person is consistent according to the things they do or the things they engage themselves and if a person can be able to identify the trends of behavior of another, he or she can be able to predict the way the first person will respond to a situation (Turner 76). According to the functionalist theory, the mental constructs exist because of its function it serves and without such, it cannot be important to the individual who has them. This means the beliefs, desires, and pain exist in the mind of a person because that person needs them to perform an action in the context he or she finds himself or herself. This implies that according to functionalist, mental constructs are void and irrelevant if they do not exist to serve any purpose in the person who has them whether they are perceivable to be good or bad (Turner 78). According to the perspective of the reductionist, a system that is complicated and has many constituents has an influence on the small constituents and they can be used to explain the constituent. According to these theorists, for example, in a society, the general culture shapes the behavior of individuals and these individuals can be used to explain the reasons why culture is the way it is. This means that the individuals in a certain context are dependent on the general context of behavior and therefore, one of them in that context can be used to explain why the groups behave the way it does (Turner 93-94). The theory of eliminative materialism argues that there are no neural bases that can be used to explain various contexts of desire or beliefs of a person since they have poor definitions.  

Is College Worth it Essay Example for Free

Is College Worth it Essay â€Å"What is a College Degree Worth? † by Maggie Gallagher. The overall main idea of this article is that the cost of college is going up and people is taking loans out which are putting them in debt because they have to pay them off. That is the reason why some people don’t go to college, I believe the author wrote the article to inform you about why teens are in debt after they graduate college. According to Mrs. Gallagher the main reason why college debt is increasing is  because loans are available and teenagers are encouraged to borrow money. At least 700 colleges have contract with bad banks to market credit cards to students. About nine in 10 students use credit cards to help pay for their college expenses. The main reason why the increase in college debt is because colleges have taught teenagers bad financial decisions, which has caused the decrease in the worth of a college degrees. The degree I’m pursuing at this moment is my Bachelor’s degree in Culinary Arts. I want a better education other than a high school diploma. Me wanting to become a chef/ Pastry chef, there is nothing Flint nor Michigan for my degree. I want to be up there with the people on the Food network channel and the TLC channel as well. With me having more degrees it will most likely guarantee me a VERY nice job in the near future.

As I Walked Out One Evening | Analysis

As I Walked Out One Evening | Analysis There is a certain level of hesitation that is often experienced when it comes to ones acceptance of time. One may see this uncertainty not only in others but perhaps in his or her own perceptions. There is much speculation surrounding time and what happens when ones time on earth finally reaches its end. The nature of time, in itself, is a scary reality. Not only does time play a very personal role in the lives of all of humanity, but it also plays a prominent part in many of the works included in modern and contemporary poetry. We see the positions of various poets when it comes to the concept of time, whether it be a position of optimism or pessimism. There is one thing that is certain, however; one never knows when his or her time on earth is up. Time is, essentially, all we have. W. H. Audens As I Walked Out One Evening, can be viewed as a prime example of a poem which revolves around the theme of the finite nature of time. A background set to match this exchange between mortality and eternity is the brimming river (5) where the speaker stops to listen to the lovers. The river is used as a metaphor for Time because of the way it flows: it goes on endlessly and goes on even as we do not. No matter what small connection we may make with the water in the flowing river, it keeps flowing past us. No matter how hard we may try we could never stop the river from flowing. Similarly, the bells of the clock tower remind us of the Time that is passingthe time that will not stop for us: The underlying theme of Time is the cycle of life or perhaps the rotation of the seasons. The speaker may already be thinking about the passing seasons of his own life when the crowds remind him of harvest wheat. Auden portrays the wheat in terms of time: fall is frequently used as a metaphor for old age. It is the final stage of the life cycle; the flowers have blossomed and the cold winter is on its way. Here the speaker sees the crowd and is perhaps reminded of the cycle we all experience as we head towards our elder years. Even the young lovers will grow pale with old age, just as into many a green valley / Drifts the appalling snow (33-34). There is tragedy that lies in beauty and youth; neither of them last and eventually we grow old and disintegrate. Auden metaphorically portrays Time in terms that are almost disturbing, as it dwells in the burrows of the nightmare (25) and watch the lovers from the shadows. It pauses just until they are about to complete their love with a kiss before it coughs and interrupts with its opposition. The same church bells that chime the hour also ring for the dead and on this night near the river both bells have the same sounds. The speaker, as he walks along the river down Bristol Street, may have found himself further down that lane than he anticipates, as he ends up somewhere between the lovers and all the clocks in the city (21). Standing there as the bells ring, he loses track of time, hearing a complete song in reply to the lovers singing. He soon realizes how much time has passed: It was late, late in the evening, / The lovers they were gone (61-62). Here, we see the speaker as he spends his time observing others. In the process, he never gets to experience his own life, on his own time. As so on as he knows it, a great deal of time has passed; so much in fact, that the lovers have gone away-indicating that they have used up their own mortal time on earth and the speaker has wasted a great deal of his own time through his relentless observation of them. The poem incorporates two different ideas conveyed by the songs. Auden ultimately invites us to evaluate the viewpoints of the lover and the clocks that are clearly at odds with one another. The lover argues that love is everlasting and eternally young while the clocks assert that all of life, including love, is subject to time and decay. Although Auden does not want o deny the lovers optimism, he ultimately gives more acknowledgment to the clocks practical outlook. The clocks song is less emotional and more detached than the lovers. They whirr and chime and dispute that time is more powerful than anything human, even love: Time watches from the shadow / And coughs when you would kiss (27-28). Time is a silent and inevitable force that disrupts even the most joyous of moments and can replace a kiss that brings people closer, with a cough that pushes them apart. The clocks uphold that Time is the triumphant force since it is a race that can never be won by humanity and there are never any exceptions to its limits nor are there any survivors of its boundaries. As the clocks describe it, In headaches and in worry / Vaguely life leaks away (29-30). The clocks go on and we see that time not only presents trivial worries such as headaches, but it also carries greater dangers: The glacier knocks in the cupboard, / The desert sighs in the bed, / And the crack in the tea-cup opens / A lane to the land of the dead. The items mentioned are all objects foun d in ones home. The greater powers of the external world can infiltrate even such personal places as the ones we call home. Even death, perhaps the greatest threat of all, can make its way into this domestic place. The cracked tea-cup represents the effects of time. It is evidence that things diminish as time goes by and it illustrates the human condition. We are, essentially, born to die because Time is bound to take its course. Auden personifies the clocks by giving them the ability to speak. In reality, these clocks do not have the capacity for human language. The clocks argument, like the lovers, may well be taking place inside the poets head. The poet is thinking about the nature of human life, and in the clocks song there are several references to vision as well as literal reflections. In one of the clocks songs, the clocks urge: O look, look in the mirror, O look in your distress; Life remains a blessing Although you cannot bless. (49-52). Here, the mirror portrays an image of sorrow while the downbeat voice of the stanza is fit by the statement that Life remains a blessing (52). Nonetheless, the clocks make it clear that humans are not capable of valuing the joys of life and give one final order: You shall love your crooked neighbour /With your crooked heart (55-56). The clocks song cuts the lovers optimism and certainty short. Auden gives the clocks three times as many stanzas as the lover to state their ideas about life, love, and time. This imbalance, along with the fact that the clocks get the last word in the discussion, demonstrates that their viewpoint is the prevailing one. The clocks do not, however, get the last word in the poem. In the final stanza, the speaker is finished quoting them and returns to speak in his own voice. Many hours have passed since the start of the poem. The crowds, along with the lovers, are gone. The sounds of clocks have stopped and the poem concludes the deep river ran on (60) This line hints towards hopefulness as it may indicate that the cycle presented in the poem will recur and that lovers as well as those who believe in love, will again sing of their hopes and passions, despite the dire assertions of clocks and other reminders of the reality of time. On the contrary, the concluding line may be disparaging-the river seems to be symbolic of times unyielding onward motion. The river appears to have little concern for the human world and is unchanged by joy and grief. In spite of the inevitability of human fate, nature and time will continue to move forward with or without us, as it has done for countless years. Auden seems to advance the clocks message over the lovers perhaps becau se he cannot refute the fact that love is stifled by the complexities and boundaries of life. On the other hand, poetry, unlike love or the life spans of human beings, has the potential to forwardly and eternally progress. As I Walked Out One Evening and other poems must end, however, poetry as a figure of human accomplishment, has the chance to live on.

Use of HPV Vaccines for Cervical Cancer Prevention

Use of HPV Vaccines for Cervical Cancer Prevention HPV Vaccines: Will They Prevent Cervical cancer Introduction Human papilloma viruses (HPV) belong to the papillomaviridae family, they are double stranded DNA viruses. HPV is the most common sexually transmitted infection (STI) in the world (Urman et al. 2008). HPV is strongly associated with cervical cancer; more than 99% what are the other causes/factors please of cervical cancer cases are positive for HPV DNA and indeed, cervical cancer is the second most common malignancy in the world (Wang et al. 2007). In developed countries the incidence of cervical cancer has been reduced significantly by the introduction of a cervical screening programme. In developing countries where 83% of mortalities due to cervical cancer occur, there are no such programmes (Parkin et al. 2006). Can the introduction of a vaccine against HPV further reduce globally the incidence of cervical cancer? Many diseases caused by viruses are controlled in the developed world by ongoing successful vaccination programmes; Polio, Measles, Mumps and Rubella are a few examples. Smallpox caused by Variola virus was eradicated in 1979 through a successful worldwide vaccination programme. The factors that affect the Polio and MMR vaccine programmes success and those that affected the successful smallpox programme may also be contributory to the success of the HPV vaccination program. Vaccination of HPV is complex and multi factorial. This investigation studies a number of factors including: Vaccine efficacy Vaccine Cost/affordability/practicality of administration Production and Distribution Government backing and financial commitment Other support organisations such as the WHO, UNICEF, Gates Foundation, Social factors Media effects Public awareness Safety, and perceived fears Currently two prophylactic vaccines against HPV types 16 and 18, the most prevalent causes of HPV have been approved by the food and drug administration (FDA). Many developed countries have already introduced vaccination programmes using one of these vaccines. Can the vaccines and programme prevent cervical cancer? In order to effectively understand the implication of such a vaccination programme we must first fully examine the causative agent (HPV) and the consequential potential diseases including the biology, history and prevalence. Human Papillomavirus Approximately 200 types of HPV are identified of which around 40 infect the genital tract (McCance 2004). The majority of HPV types cause no symptoms, some types can cause warts and a minority may lead to cancer. Genital HPVs are transmitted via sexual contact, mainly intercourse, with an infected individual, and the risk of developing an HPV infection generally increases with the number of sexual partners, the sexual history of that partner or the introduction of a new sexual partner. Studies have shown that at least one type of HPV infection occurs soon after sexual debut, with around 30% of women infected with at least one high risk type within two years (Winer et al 2003; Winer et al 2008). HPVs are classified as either high risk or low risk, on the basis of association with cervical cancer. There are 15 types classified as high risk and three as probable high risk. High risk types include 16,18,31,33,35,39,,45,51,52,56,58,59,68,73,probable high risk types include 26,53,66 Low risk types include 6,11,40,42,43,54,61,70,72,81 and CP6108. More than 99% of cervical cancers are associated with HPV, of these 70% are associated with HPV type 16 and 18, with HPV 16 causing 50% and HPV 18 causing more than 15% in Europe (Smith et al..2007). HPV 16 is thus the single, most common high risk HPV. Interestingly HPV types 16 and 18 also cause 80% of anal cancer and 30% of vaginal and why the difference in % oper area research needed here.vulvar cancer and are associated with cancers of the, oropharynx and some rare cancers of the head and neck. (add reference form cervical cancer burden worldwide paper) The majority of HPV infections are asymptomatic, self limiting, and transient, with 70% of new HPV high risk type infections cleared within one year (with the median duration of an infection at 8 months) and 90% within two years (Ho et al 1998). The transient infection usually causes no clinical problems. A small proportion of high risk type infections persist due to host immune evasion, an evasion that results not only from restriction of HPVs to sites that are relatively inaccessible to host defences but also due to several mechanisms of preventing immune response what are these mechanisms please (a sk Dick if this is what he means . This persistence is the most important factor in the development of pre cancerous and cancerous lesions. The time span between infection by HPV and the development of pre cancerous lesions or cervical carcinoma varies from one to ten years (Moscicki et al 2006) and up to 20 years from other sources. HPV show little evidence of dramatic adaptability with phylogenic studies suggesting that the biology of HPVs has remained the same for over 200,000 years (Halpren et al 2000). While HPVs show historically the influence of point mutations, inserts, deletions and duplications, the predominant pattern of mutation within a given type is point mutation, with large scale rearrangements within the most conserved genes of HPVs such as L1 being rare (Myers et al 1996). Intra patient variation within HPV types is uncommon due to their low mutation rate. This low mutation rate is directly linked to the HPV replication strategy that requires host cell machinery, which has stringent proof reading mechanisms that avoid the incorporation of errors, conferring slow mutagenesis. All HPVs exhibit extreme specificity for infection of epithelial cells and do not infect or express their gene products in the underlying dermis. Although the mechanism of infection is not fully understood, the HPV epitheliotrophy resides for the most part in the interaction of specific transcription factors with the viral regulatory region known as the long control region (LCR). Infection with HPV can result in hyperproliferation of the host cell, and with certain high risk HPV types it may lead to transformation and immortalization. This is because high risk HPVs express two or more protein products (E6, E7 and E5) that transiently disrupt the cell cycle and stimulate cell division, knocking out at the same time the cellular mechanisms for growth inhibition. For a productive infection, HPVs require terminally differentiated cells. This HPV biology feature has impeded studies on the full reproduction life cycle because of the lack of highly efficient models of epithelial terminal di fferentiation in vitro. Most of the different stages in the HPV life cycle have been established using genetic engineering and molecular biology strategies. The dsDNA of HPV exists in a non enveloped icosahedral shaped virion 52-55 nm in diameter. The dsDNA genome is circularised and around 8000base pairs in length (Fig1). The genome encodes eight proteins, six early E1, E2, E4, E5, E6, E7, and two late structural proteins L1 and L2 and the previously mentioned noncoding LCR. Fig 1 HPV type 16 Genome structure, gene and functional domain location http://www.dnachip-link.com/Eng/library/HPV.aspusg 15/11/20009 Fig 1 shows the dsDNA genome of HPV type 16, and the location of the early and late genes along with the LCR that contains the origin of replication. An initial infection requires the access of infectious particles to the basal layer of the epithelium. Some HPVs require a break in the stratified epithelium to achieve this. Such breaks are not necessarily obvious and may occur under conditions where the skin is exposed to water or abraded, or subjected to an environment where micro traumas may occur such as possibly in aswiming pool or ect (must put an example)(in fig 2 shows as a cut). Following infection and uncoating it is thought that the virus maintains its genome as an episome in low copy numbers within basal cells of the epithelium. Although the pattern of gene expression in these cells is not well understood, it is generally thought that viral proteins E1 and E2 are expressed to maintain the viral DNA episome (Wilson et al.2002) and possibly to facilitate the segregation of genomes during cell division (You et all.2004). It is not known whether viral transformation proteins E6 and E7 are also expressed in the basal layer, but it does appear that initial infection is followed by a proliferative phase that results in the increase in the number of basal cells harbouring viral episomes. In normal uninfected epithelium, basal cells leave the cell cycle soon after migration into the superbasal cell layers where they undergo a process of terminal differentiation. During infection E6 and E7 are expressed in these cells stopping normal differentiation (Sherman et all.1997). E6 and E7 are believed to work together to achieve this and in lesions caused by high risk HPV types. During a natural infection the ability of E7 to stimulate S-phase progression is limited to a subset of differentiated cells with low levels of p21/p27, or which express high enough levels of E7 to overcome the block in S-phase entry. The viral E6 protein is thought to prevent apoptosis in response to unscheduled S-phase entry brought on by E7. The association of E6 with p53 and the inactivation of p53 mediated growth suppression and apoptosis is well documented, E6 may also associate with other pro-apoptotic proteins including bak (Thomas and Banks,1998) and bax (Li and Dou,2000). E6 is thus considered a predisposing factor in the development of HPV associated cancers, allowing the accumulation of chance errors in host DNA to go unchecked. Furthermore the E6 protein of high risk HPVs can stimulate cell proliferation independently of E7 via a c-terminal PDZ ligand binding domain. E6 PDZ is enough to mediate superbasal cell proliferation and may contribute to the formation of metastatic tumours by disrupting normal cell adhesion (Nguyen et al.2003) Amplification of the viral genome and the ability to package these genomes into infectious particles is essential for the production of infectious virions. For most HPV types this occurs in the mid or upper epithelial layers following an increase in activity of the late promoter. The late promoter gene is located within the E7 open reading frame, and the upregulation of the late promoter is thought to lead to increased expression of proteins involved in viral DNA replication, without directly affecting the expression of E6 or E7 necessary for S-phase entry. The amplification of the viral genome begins in a subset of cells in the proliferative compartment and requires the expression of all viral early gene products, these include E4 and E5 whose role in replication is not yet clearly understood. Binding of E2 to the HPV upstream regulator region is essential for viral DNA replication that is dependent on the differentiated state of epithelial cells. E2 recruits the E1 DNA helicase to the viral origin of replication. Throughout the virus life cycle, the relative levels of viral proteins are controlled by promoter usage and by differential splice site selection, with an increase in E1 and E2 allowing an increase in viral copy numbers in the upper epithelial layers. Current models suggest that a small increase in promoter activation during differentiation may lead to an increase in the level of E1 and E2 and a subsequent increase in genome copy number. The newly replicated genome could then serve as a further template for expression of E1 and E2, facilitating the amplification of viral genome and in turn further expression of E1 and E2 replication proteins. Viral DNA remains latent (not integrated) in basal cells of benign lesions. Replication occurs in the differentiating cells where capsid proteins and viral particles are found. Viral DNA is integrated in cancer cells, which contain no replicating virus. Once viral genome replication is completed, the expression of two virally encoded structural proteins, expressed in the upper layers of infected epithelia may occur. L1 the major capsid protein is expressed after L2 in a sub set of cells that express E4 (fig 2), this allows the assembly of infectious particles in the upper layers of the epithelium (Florin et al.,2002). A successful infection requires the virus to escape from the infected skin cell and survive extracellularly prior to re-infection. HPVs are non-lytic and are as such not released until the infected cells reach the epithelial surface. The intracellular retention of HPV antigen until the cell reaches the uppermost epithelial layers may contribute the compromised immune detection, especially as the virus has molecular mechanisms that limit the presentation of viral epitopes to the immune system in the lower epithelial layers (Ashrafi et al 2002). What are these mechanisms Figure 2 Papillomavirus type 16 Life Cycle and gene expression location within epithelium Taken from, The papillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Figure 2 diagrammatic representation of the skin with HPV type 16 gene expression incorporated, colour of arrows are representative of genes expressed within epithelial cells. The frequent detection of high risk HPV DNA in cervical lesions in the absence of any obvious disease, may be explained by the presence of the virus in a latent state, with only very few cells able to support the productive virus life cycle during epithelial cell differentiation. Following immune regression, HPV DNA is thought to remain in the basal epithelial cells waiting to be reactivated once levels of immune surveillance decline there are conflicting opinions (Zhang et al.1999). If regression is not achieved lesions may persist and in some instances progress to cancer. The number of lesion that progress to cancer is very low when compared to the prevalence of high risk HPV infection in the general public. The Progression of productive lesion to high grade lesions may result from the deregulation ( what happen to allow thes proteins to be deregulated intergrattion loss of E2 adn p53 association, be specific add biochemistry here please. in the expression of transforming proteins E6 and E7. The inability of a cell to support the whole virus life cycle is often associated with the development of cancerous lesions. The transformation zone (Fig 3) is particularly susceptible to cervical cancer; it appears that high risk types of HPV such as type 16 cannot complete their life cycle at this site Progression from CIN3 to cancer usually occurs in lesions that contain integrated copies of the viral genome in which E7 expression is elevated. Suggesting that retention of E6 and E7genes and the loss of E2 and E4 genes (that exert negative effect on cell growth) usually accompanies the development of invasive cancer. (reference) Remember for CIN refer to in that section or here but Cin must be corrulated with what causes the cancer and with whats happening with the virus that causes the change in CIN or the causes in CIN to occur. Cervical cancerisa considerable contributor to morbidity and mortality. Being the second most common cancer worldwide and the twelfth most common cancer in women in the UK. Cervical cancer in 2002 was the cause of 274,000 deaths worldwide (the most current data available)REF THIS FIGURE and continues to causes more than 1000 deaths in the UK each year. There are two main types of cervical cancer squamous cell cancer (the most common) and adenocarcinoma, although they are often mixed. They are named after the types of cell that become cancerous through neoplasia. Squamous cells are flat cells covering the cervix; adenomatous cells are found in the passageway from the cervix to the womb. Other rarer cancers of the cervix include small cell cancer. Deaths from cervical cancer in the UK have fallen over the last 20 years mainly because of the NHS cervical screening programme that reduced the mortality rates by 62% between 1987-2006. Screening may detect changes in the cells of the cervix at a pre-cancerous stage. Fig 3 TITTLE Showing location of transformation zone. Cell samples are examined for abnormalities, these abnormality are described in a standard format covering cytology and/or histology. What are these standard format CIN 1 CIN2 CIN3 LISL LGSIL HSIL HGSIL USE FIG 4 and explain whats happening with the proteins expressed and genome intergration where CIN number progression is concerned please. MUST DO From Lowy Schiller, J Clin Invest, 116:1167-73, 2006 Low grade squamous intraepithelial lesion (LSIL or LGSIL) indicates possiblecone biopsy, or laser ablation. High grade squamous intraepithelial lesion (HSIL or HGSIL) indicates moderate or severeCIN 2 or CIN3 (fig 3). While cervical screening has reduced the mortality significantly in the developed world cervical cancer is still a significant burden worldwide. Fig 4 Taken from, The popillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Fig. 5. CIN 1 resembles productive infections caused by other HPV types and as such is the most benign form of cervical intraepithelial neoplasia , it is confined to the basal 1/3 of the epithelium, CIN 2 Moderate dysplasia confined to the basal 2/3 of the epithelium,CIN3 Sever dysplasia that spans more than 2/3 of the epithelium, and may involve the full thickness. INCIDENCE An estimated 493,000 new cases and 274,000 deaths in 2002 were caused by cervical cancer. The vast majority, some 83% of these cases, occur in developing countries, where cervical cancer amounts to 15% of female cancers with a risk before age 65 of 1.5%. In developed countries cervical cancer accounts for only 3.6%, with a risk of 0.8% before age 65. REF The highest incidence rates are observed in Sub-Saharan Africa, Melanesia, Latin America and the Caribbean, South-Central Asia, and South East Asia (fig 6) Fig 6 Worldwide Burden of HPV related Cervical Cancer Figures from 2002. Parkin MD et al 2006 The burden of HPV-related cervical cancers The vast majority of cervical cancers are squamous cell carcinoma adenocarcinomas being less common (fig 6). Generally the proportion of adenocarcinoma cases is higher in areas with low incidence of cervical cancer, accounting for up to 25% of cases in western countries (fig 6). This higher incidence of adenocarcinoma may be partially explained by cytological screening, which historically, had little effect in reducing the risk of adenocarcinoma of the cervix, because these cancers, and their precursors, occur within the cervical canal, and were not readily sampled by scraping of the epithelium of the ectocervix. Fig 5 Fig 5 showing the higher % of adenocarcinoma in counties that have screening programmes such as the UK and Denmark What is this showing? Make it clear.do you really need it. MORTALITY RATES Mortality rates are substantially lower than incidence rates. Worldwide 55% (could you double chek that this is the case please misses) of all those that develop the disease die, the figures vary significantly from the developed to the developing world. Low risk regions of the west such as Europe have a death rate of 37% while in developing countries where many cases present at relatively advanced stages, death rates are significantly higher increasing to 70%. Cervical screening programmes in the developed world identify pre-cancerous lesions at a stage where they can be easily treated accounting for the difference in mortality rates. TITTLE IF and figure number staying and refer to in text As cervical cancer affects a relatively high number of young women, it is a significant cause of years of life lost (YLL) in the developing world. Yang et al 2004 found that cervical cancer was responsible for the 2.7 million (age weighted) years of lives lost world wide in 2000, and that it is the single biggest cause of years of life lost from cancer in the developing world. In Latin America, Eastern Europe and the Caribbean, cervical cancer makes a greater contribution to YLL than disease such as Tuberculosis or AIDS. HPV is also associated with many other forms of cancer that could possibly be prevented with use of HPV vaccines; cancers of the penis, anus, vulva, vagina, oropharynx and some rare cancers of the head and neck are included. However cancer of the cervix is by far the most significant, in terms of incidence and mortality (table 1). Cancer of the vulva and vagina have a significantly lower incidence rate compared to cervical cancer, however since 80% of the incidence are caused by HPV types 16 or 18 women vaccinated against these types would also be protected against these forms of cancer. Incidence of squamous cell carcinoma of the anus are twice as common in females as males with HPV types 16 and 18 accounting for 83% of all cases. There is a particularly high incidence of anal cancer among homosexual males, shown by the high incidence rate in populations such as Sanfransisco, where gay incidence are higher than average (fig 7). Globally cancer of the penis is relatively rare accounting for 0.5% of cancers in men (table 1). HPV DNA is detectable in 40-50% of all penile cancers and serological studies have confirmed the role of HPV 16 and 18 (IARC 2005). Cancers of the mouth and oropharynx caused by HPV are very low at 0.06% of all cancers with 0.05% being caused by HPV types 16/18. Due to the small size of most studies and the absence of comparable measurements of prevalence of infection in normal subjects conducted for cancers of the vulva, vagina, penis and anus true prevalence is difficult to quantify. The figures shown in table 1, imply that we are dealing with a virus that discriminates primarily through disease aginst women, in particular young women. Gay men, however are also clearly an at risk group. Currently only young women are vaccinated aginst HPV types 16 and 18, however the JCVI (joint committee on vaccination and immunisation) have noted that the vaccines has not been conclusively trialled on men, and that there is insufficient evidence that the vaccine available would protect against anal, penile or head and neck cancer. However when more data becomes available they will consider vaccinating, high risk groups such as men who have sex with men. Add what this implies for prophylactic use of vaccine with other cancers cause by HPV And what you think about the ue of vaccine on highrisk men and its effectivity against other cancers caused by HPV types 16 and 18. Fig 7 TITTLE add Figure 6 showing that cancer of the anus are more prevalent in women than men with the major noted exception being San Francisco, where the increased incidence can be explained by a large number of homosexual men. Table 3 VACCINATION An effective vaccine should stimulate a suitable range of immune responses, mimic or improve on the protection gained from a wild type infection with little side effects. Critically the vaccine should be inexpensive, easily administered, transported and stored to further reduce cost and maximise convenience, this is especially relevant in the case of HPV vaccine as those that are not protected by the screening programmes of the developed world would benefit the most, ease of administration and storage is paramount in the developing world as stability and healthcare is more sporadic, and people are often more remote. There are many different kinds of vaccines available, and different vaccines have a variety qualities and limitations. Live attenuated vaccines contain a version of the pathogenic microbe that is avirulent, they often elicit an excellent cellular and antibody response with good longevity that can be lifelong with few doses. However there is always the possibility that the vaccine may revert to its virulent form, causing disease. For this reason a live attenuated vaccine is not appropriate for use against oncogenic HPV types. Recombinant vaccines can include one or more proteins that may illicit an immune response. A process has been developed to allow the removal of the genome from an attenuated or avirulent viral vector allowing the insertion of selected genetic material or proteins from another virus. The carrier viruses then ferry that viral DNA into host cells where the genes are expressed. Recombinant vaccines closely mimic a natural infection and therefore illicit a strong immune system. Inactivated vaccines are produced by killing the disease causing microbe by chemical (formaldehyde eg just double check), heat or radioactive means. These vaccines are more stable than live vaccines, and as there is no risk of reversion to virulence. They are also safer than live vaccines. Most inactivated vaccines stimulate a weaker immune response than live vaccines and several doses or boosters may be required to maintain immunity. DNA vaccines dispense with both the whole organism and its parts. They only include the essential part of the microbes genetic material. In particular, DNA vaccines use the genes that code for immunogens. Researchers have found that when the genes for a microbes antigens are introduced into the body, some cells will take up that DNA. The DNA then instructs those cells to make the antigen molecules. The cells secrete the antigens and display them on their surfaces. In other words, the bodys own cells become vaccine-making factories, creating the antigens necessary to stimulate the immune system. A DNA vaccine against a microbe would evoke a strong antibody response to the free antigen secreted by cells, and also stimulate a strong cellular response against the microbial antigens displayed on cell surfaces. The DNA vaccine is unable to cause disease Use of HPV Vaccines for Cervical Cancer Prevention Use of HPV Vaccines for Cervical Cancer Prevention HPV Vaccines: Will They Prevent Cervical cancer Introduction Human papilloma viruses (HPV) belong to the papillomaviridae family, they are double stranded DNA viruses. HPV is the most common sexually transmitted infection (STI) in the world (Urman et al. 2008). HPV is strongly associated with cervical cancer; more than 99% what are the other causes/factors please of cervical cancer cases are positive for HPV DNA and indeed, cervical cancer is the second most common malignancy in the world (Wang et al. 2007). In developed countries the incidence of cervical cancer has been reduced significantly by the introduction of a cervical screening programme. In developing countries where 83% of mortalities due to cervical cancer occur, there are no such programmes (Parkin et al. 2006). Can the introduction of a vaccine against HPV further reduce globally the incidence of cervical cancer? Many diseases caused by viruses are controlled in the developed world by ongoing successful vaccination programmes; Polio, Measles, Mumps and Rubella are a few examples. Smallpox caused by Variola virus was eradicated in 1979 through a successful worldwide vaccination programme. The factors that affect the Polio and MMR vaccine programmes success and those that affected the successful smallpox programme may also be contributory to the success of the HPV vaccination program. Vaccination of HPV is complex and multi factorial. This investigation studies a number of factors including: Vaccine efficacy Vaccine Cost/affordability/practicality of administration Production and Distribution Government backing and financial commitment Other support organisations such as the WHO, UNICEF, Gates Foundation, Social factors Media effects Public awareness Safety, and perceived fears Currently two prophylactic vaccines against HPV types 16 and 18, the most prevalent causes of HPV have been approved by the food and drug administration (FDA). Many developed countries have already introduced vaccination programmes using one of these vaccines. Can the vaccines and programme prevent cervical cancer? In order to effectively understand the implication of such a vaccination programme we must first fully examine the causative agent (HPV) and the consequential potential diseases including the biology, history and prevalence. Human Papillomavirus Approximately 200 types of HPV are identified of which around 40 infect the genital tract (McCance 2004). The majority of HPV types cause no symptoms, some types can cause warts and a minority may lead to cancer. Genital HPVs are transmitted via sexual contact, mainly intercourse, with an infected individual, and the risk of developing an HPV infection generally increases with the number of sexual partners, the sexual history of that partner or the introduction of a new sexual partner. Studies have shown that at least one type of HPV infection occurs soon after sexual debut, with around 30% of women infected with at least one high risk type within two years (Winer et al 2003; Winer et al 2008). HPVs are classified as either high risk or low risk, on the basis of association with cervical cancer. There are 15 types classified as high risk and three as probable high risk. High risk types include 16,18,31,33,35,39,,45,51,52,56,58,59,68,73,probable high risk types include 26,53,66 Low risk types include 6,11,40,42,43,54,61,70,72,81 and CP6108. More than 99% of cervical cancers are associated with HPV, of these 70% are associated with HPV type 16 and 18, with HPV 16 causing 50% and HPV 18 causing more than 15% in Europe (Smith et al..2007). HPV 16 is thus the single, most common high risk HPV. Interestingly HPV types 16 and 18 also cause 80% of anal cancer and 30% of vaginal and why the difference in % oper area research needed here.vulvar cancer and are associated with cancers of the, oropharynx and some rare cancers of the head and neck. (add reference form cervical cancer burden worldwide paper) The majority of HPV infections are asymptomatic, self limiting, and transient, with 70% of new HPV high risk type infections cleared within one year (with the median duration of an infection at 8 months) and 90% within two years (Ho et al 1998). The transient infection usually causes no clinical problems. A small proportion of high risk type infections persist due to host immune evasion, an evasion that results not only from restriction of HPVs to sites that are relatively inaccessible to host defences but also due to several mechanisms of preventing immune response what are these mechanisms please (a sk Dick if this is what he means . This persistence is the most important factor in the development of pre cancerous and cancerous lesions. The time span between infection by HPV and the development of pre cancerous lesions or cervical carcinoma varies from one to ten years (Moscicki et al 2006) and up to 20 years from other sources. HPV show little evidence of dramatic adaptability with phylogenic studies suggesting that the biology of HPVs has remained the same for over 200,000 years (Halpren et al 2000). While HPVs show historically the influence of point mutations, inserts, deletions and duplications, the predominant pattern of mutation within a given type is point mutation, with large scale rearrangements within the most conserved genes of HPVs such as L1 being rare (Myers et al 1996). Intra patient variation within HPV types is uncommon due to their low mutation rate. This low mutation rate is directly linked to the HPV replication strategy that requires host cell machinery, which has stringent proof reading mechanisms that avoid the incorporation of errors, conferring slow mutagenesis. All HPVs exhibit extreme specificity for infection of epithelial cells and do not infect or express their gene products in the underlying dermis. Although the mechanism of infection is not fully understood, the HPV epitheliotrophy resides for the most part in the interaction of specific transcription factors with the viral regulatory region known as the long control region (LCR). Infection with HPV can result in hyperproliferation of the host cell, and with certain high risk HPV types it may lead to transformation and immortalization. This is because high risk HPVs express two or more protein products (E6, E7 and E5) that transiently disrupt the cell cycle and stimulate cell division, knocking out at the same time the cellular mechanisms for growth inhibition. For a productive infection, HPVs require terminally differentiated cells. This HPV biology feature has impeded studies on the full reproduction life cycle because of the lack of highly efficient models of epithelial terminal di fferentiation in vitro. Most of the different stages in the HPV life cycle have been established using genetic engineering and molecular biology strategies. The dsDNA of HPV exists in a non enveloped icosahedral shaped virion 52-55 nm in diameter. The dsDNA genome is circularised and around 8000base pairs in length (Fig1). The genome encodes eight proteins, six early E1, E2, E4, E5, E6, E7, and two late structural proteins L1 and L2 and the previously mentioned noncoding LCR. Fig 1 HPV type 16 Genome structure, gene and functional domain location http://www.dnachip-link.com/Eng/library/HPV.aspusg 15/11/20009 Fig 1 shows the dsDNA genome of HPV type 16, and the location of the early and late genes along with the LCR that contains the origin of replication. An initial infection requires the access of infectious particles to the basal layer of the epithelium. Some HPVs require a break in the stratified epithelium to achieve this. Such breaks are not necessarily obvious and may occur under conditions where the skin is exposed to water or abraded, or subjected to an environment where micro traumas may occur such as possibly in aswiming pool or ect (must put an example)(in fig 2 shows as a cut). Following infection and uncoating it is thought that the virus maintains its genome as an episome in low copy numbers within basal cells of the epithelium. Although the pattern of gene expression in these cells is not well understood, it is generally thought that viral proteins E1 and E2 are expressed to maintain the viral DNA episome (Wilson et al.2002) and possibly to facilitate the segregation of genomes during cell division (You et all.2004). It is not known whether viral transformation proteins E6 and E7 are also expressed in the basal layer, but it does appear that initial infection is followed by a proliferative phase that results in the increase in the number of basal cells harbouring viral episomes. In normal uninfected epithelium, basal cells leave the cell cycle soon after migration into the superbasal cell layers where they undergo a process of terminal differentiation. During infection E6 and E7 are expressed in these cells stopping normal differentiation (Sherman et all.1997). E6 and E7 are believed to work together to achieve this and in lesions caused by high risk HPV types. During a natural infection the ability of E7 to stimulate S-phase progression is limited to a subset of differentiated cells with low levels of p21/p27, or which express high enough levels of E7 to overcome the block in S-phase entry. The viral E6 protein is thought to prevent apoptosis in response to unscheduled S-phase entry brought on by E7. The association of E6 with p53 and the inactivation of p53 mediated growth suppression and apoptosis is well documented, E6 may also associate with other pro-apoptotic proteins including bak (Thomas and Banks,1998) and bax (Li and Dou,2000). E6 is thus considered a predisposing factor in the development of HPV associated cancers, allowing the accumulation of chance errors in host DNA to go unchecked. Furthermore the E6 protein of high risk HPVs can stimulate cell proliferation independently of E7 via a c-terminal PDZ ligand binding domain. E6 PDZ is enough to mediate superbasal cell proliferation and may contribute to the formation of metastatic tumours by disrupting normal cell adhesion (Nguyen et al.2003) Amplification of the viral genome and the ability to package these genomes into infectious particles is essential for the production of infectious virions. For most HPV types this occurs in the mid or upper epithelial layers following an increase in activity of the late promoter. The late promoter gene is located within the E7 open reading frame, and the upregulation of the late promoter is thought to lead to increased expression of proteins involved in viral DNA replication, without directly affecting the expression of E6 or E7 necessary for S-phase entry. The amplification of the viral genome begins in a subset of cells in the proliferative compartment and requires the expression of all viral early gene products, these include E4 and E5 whose role in replication is not yet clearly understood. Binding of E2 to the HPV upstream regulator region is essential for viral DNA replication that is dependent on the differentiated state of epithelial cells. E2 recruits the E1 DNA helicase to the viral origin of replication. Throughout the virus life cycle, the relative levels of viral proteins are controlled by promoter usage and by differential splice site selection, with an increase in E1 and E2 allowing an increase in viral copy numbers in the upper epithelial layers. Current models suggest that a small increase in promoter activation during differentiation may lead to an increase in the level of E1 and E2 and a subsequent increase in genome copy number. The newly replicated genome could then serve as a further template for expression of E1 and E2, facilitating the amplification of viral genome and in turn further expression of E1 and E2 replication proteins. Viral DNA remains latent (not integrated) in basal cells of benign lesions. Replication occurs in the differentiating cells where capsid proteins and viral particles are found. Viral DNA is integrated in cancer cells, which contain no replicating virus. Once viral genome replication is completed, the expression of two virally encoded structural proteins, expressed in the upper layers of infected epithelia may occur. L1 the major capsid protein is expressed after L2 in a sub set of cells that express E4 (fig 2), this allows the assembly of infectious particles in the upper layers of the epithelium (Florin et al.,2002). A successful infection requires the virus to escape from the infected skin cell and survive extracellularly prior to re-infection. HPVs are non-lytic and are as such not released until the infected cells reach the epithelial surface. The intracellular retention of HPV antigen until the cell reaches the uppermost epithelial layers may contribute the compromised immune detection, especially as the virus has molecular mechanisms that limit the presentation of viral epitopes to the immune system in the lower epithelial layers (Ashrafi et al 2002). What are these mechanisms Figure 2 Papillomavirus type 16 Life Cycle and gene expression location within epithelium Taken from, The papillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Figure 2 diagrammatic representation of the skin with HPV type 16 gene expression incorporated, colour of arrows are representative of genes expressed within epithelial cells. The frequent detection of high risk HPV DNA in cervical lesions in the absence of any obvious disease, may be explained by the presence of the virus in a latent state, with only very few cells able to support the productive virus life cycle during epithelial cell differentiation. Following immune regression, HPV DNA is thought to remain in the basal epithelial cells waiting to be reactivated once levels of immune surveillance decline there are conflicting opinions (Zhang et al.1999). If regression is not achieved lesions may persist and in some instances progress to cancer. The number of lesion that progress to cancer is very low when compared to the prevalence of high risk HPV infection in the general public. The Progression of productive lesion to high grade lesions may result from the deregulation ( what happen to allow thes proteins to be deregulated intergrattion loss of E2 adn p53 association, be specific add biochemistry here please. in the expression of transforming proteins E6 and E7. The inability of a cell to support the whole virus life cycle is often associated with the development of cancerous lesions. The transformation zone (Fig 3) is particularly susceptible to cervical cancer; it appears that high risk types of HPV such as type 16 cannot complete their life cycle at this site Progression from CIN3 to cancer usually occurs in lesions that contain integrated copies of the viral genome in which E7 expression is elevated. Suggesting that retention of E6 and E7genes and the loss of E2 and E4 genes (that exert negative effect on cell growth) usually accompanies the development of invasive cancer. (reference) Remember for CIN refer to in that section or here but Cin must be corrulated with what causes the cancer and with whats happening with the virus that causes the change in CIN or the causes in CIN to occur. Cervical cancerisa considerable contributor to morbidity and mortality. Being the second most common cancer worldwide and the twelfth most common cancer in women in the UK. Cervical cancer in 2002 was the cause of 274,000 deaths worldwide (the most current data available)REF THIS FIGURE and continues to causes more than 1000 deaths in the UK each year. There are two main types of cervical cancer squamous cell cancer (the most common) and adenocarcinoma, although they are often mixed. They are named after the types of cell that become cancerous through neoplasia. Squamous cells are flat cells covering the cervix; adenomatous cells are found in the passageway from the cervix to the womb. Other rarer cancers of the cervix include small cell cancer. Deaths from cervical cancer in the UK have fallen over the last 20 years mainly because of the NHS cervical screening programme that reduced the mortality rates by 62% between 1987-2006. Screening may detect changes in the cells of the cervix at a pre-cancerous stage. Fig 3 TITTLE Showing location of transformation zone. Cell samples are examined for abnormalities, these abnormality are described in a standard format covering cytology and/or histology. What are these standard format CIN 1 CIN2 CIN3 LISL LGSIL HSIL HGSIL USE FIG 4 and explain whats happening with the proteins expressed and genome intergration where CIN number progression is concerned please. MUST DO From Lowy Schiller, J Clin Invest, 116:1167-73, 2006 Low grade squamous intraepithelial lesion (LSIL or LGSIL) indicates possiblecone biopsy, or laser ablation. High grade squamous intraepithelial lesion (HSIL or HGSIL) indicates moderate or severeCIN 2 or CIN3 (fig 3). While cervical screening has reduced the mortality significantly in the developed world cervical cancer is still a significant burden worldwide. Fig 4 Taken from, The popillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Fig. 5. CIN 1 resembles productive infections caused by other HPV types and as such is the most benign form of cervical intraepithelial neoplasia , it is confined to the basal 1/3 of the epithelium, CIN 2 Moderate dysplasia confined to the basal 2/3 of the epithelium,CIN3 Sever dysplasia that spans more than 2/3 of the epithelium, and may involve the full thickness. INCIDENCE An estimated 493,000 new cases and 274,000 deaths in 2002 were caused by cervical cancer. The vast majority, some 83% of these cases, occur in developing countries, where cervical cancer amounts to 15% of female cancers with a risk before age 65 of 1.5%. In developed countries cervical cancer accounts for only 3.6%, with a risk of 0.8% before age 65. REF The highest incidence rates are observed in Sub-Saharan Africa, Melanesia, Latin America and the Caribbean, South-Central Asia, and South East Asia (fig 6) Fig 6 Worldwide Burden of HPV related Cervical Cancer Figures from 2002. Parkin MD et al 2006 The burden of HPV-related cervical cancers The vast majority of cervical cancers are squamous cell carcinoma adenocarcinomas being less common (fig 6). Generally the proportion of adenocarcinoma cases is higher in areas with low incidence of cervical cancer, accounting for up to 25% of cases in western countries (fig 6). This higher incidence of adenocarcinoma may be partially explained by cytological screening, which historically, had little effect in reducing the risk of adenocarcinoma of the cervix, because these cancers, and their precursors, occur within the cervical canal, and were not readily sampled by scraping of the epithelium of the ectocervix. Fig 5 Fig 5 showing the higher % of adenocarcinoma in counties that have screening programmes such as the UK and Denmark What is this showing? Make it clear.do you really need it. MORTALITY RATES Mortality rates are substantially lower than incidence rates. Worldwide 55% (could you double chek that this is the case please misses) of all those that develop the disease die, the figures vary significantly from the developed to the developing world. Low risk regions of the west such as Europe have a death rate of 37% while in developing countries where many cases present at relatively advanced stages, death rates are significantly higher increasing to 70%. Cervical screening programmes in the developed world identify pre-cancerous lesions at a stage where they can be easily treated accounting for the difference in mortality rates. TITTLE IF and figure number staying and refer to in text As cervical cancer affects a relatively high number of young women, it is a significant cause of years of life lost (YLL) in the developing world. Yang et al 2004 found that cervical cancer was responsible for the 2.7 million (age weighted) years of lives lost world wide in 2000, and that it is the single biggest cause of years of life lost from cancer in the developing world. In Latin America, Eastern Europe and the Caribbean, cervical cancer makes a greater contribution to YLL than disease such as Tuberculosis or AIDS. HPV is also associated with many other forms of cancer that could possibly be prevented with use of HPV vaccines; cancers of the penis, anus, vulva, vagina, oropharynx and some rare cancers of the head and neck are included. However cancer of the cervix is by far the most significant, in terms of incidence and mortality (table 1). Cancer of the vulva and vagina have a significantly lower incidence rate compared to cervical cancer, however since 80% of the incidence are caused by HPV types 16 or 18 women vaccinated against these types would also be protected against these forms of cancer. Incidence of squamous cell carcinoma of the anus are twice as common in females as males with HPV types 16 and 18 accounting for 83% of all cases. There is a particularly high incidence of anal cancer among homosexual males, shown by the high incidence rate in populations such as Sanfransisco, where gay incidence are higher than average (fig 7). Globally cancer of the penis is relatively rare accounting for 0.5% of cancers in men (table 1). HPV DNA is detectable in 40-50% of all penile cancers and serological studies have confirmed the role of HPV 16 and 18 (IARC 2005). Cancers of the mouth and oropharynx caused by HPV are very low at 0.06% of all cancers with 0.05% being caused by HPV types 16/18. Due to the small size of most studies and the absence of comparable measurements of prevalence of infection in normal subjects conducted for cancers of the vulva, vagina, penis and anus true prevalence is difficult to quantify. The figures shown in table 1, imply that we are dealing with a virus that discriminates primarily through disease aginst women, in particular young women. Gay men, however are also clearly an at risk group. Currently only young women are vaccinated aginst HPV types 16 and 18, however the JCVI (joint committee on vaccination and immunisation) have noted that the vaccines has not been conclusively trialled on men, and that there is insufficient evidence that the vaccine available would protect against anal, penile or head and neck cancer. However when more data becomes available they will consider vaccinating, high risk groups such as men who have sex with men. Add what this implies for prophylactic use of vaccine with other cancers cause by HPV And what you think about the ue of vaccine on highrisk men and its effectivity against other cancers caused by HPV types 16 and 18. Fig 7 TITTLE add Figure 6 showing that cancer of the anus are more prevalent in women than men with the major noted exception being San Francisco, where the increased incidence can be explained by a large number of homosexual men. Table 3 VACCINATION An effective vaccine should stimulate a suitable range of immune responses, mimic or improve on the protection gained from a wild type infection with little side effects. Critically the vaccine should be inexpensive, easily administered, transported and stored to further reduce cost and maximise convenience, this is especially relevant in the case of HPV vaccine as those that are not protected by the screening programmes of the developed world would benefit the most, ease of administration and storage is paramount in the developing world as stability and healthcare is more sporadic, and people are often more remote. There are many different kinds of vaccines available, and different vaccines have a variety qualities and limitations. Live attenuated vaccines contain a version of the pathogenic microbe that is avirulent, they often elicit an excellent cellular and antibody response with good longevity that can be lifelong with few doses. However there is always the possibility that the vaccine may revert to its virulent form, causing disease. For this reason a live attenuated vaccine is not appropriate for use against oncogenic HPV types. Recombinant vaccines can include one or more proteins that may illicit an immune response. A process has been developed to allow the removal of the genome from an attenuated or avirulent viral vector allowing the insertion of selected genetic material or proteins from another virus. The carrier viruses then ferry that viral DNA into host cells where the genes are expressed. Recombinant vaccines closely mimic a natural infection and therefore illicit a strong immune system. Inactivated vaccines are produced by killing the disease causing microbe by chemical (formaldehyde eg just double check), heat or radioactive means. These vaccines are more stable than live vaccines, and as there is no risk of reversion to virulence. They are also safer than live vaccines. Most inactivated vaccines stimulate a weaker immune response than live vaccines and several doses or boosters may be required to maintain immunity. DNA vaccines dispense with both the whole organism and its parts. They only include the essential part of the microbes genetic material. In particular, DNA vaccines use the genes that code for immunogens. Researchers have found that when the genes for a microbes antigens are introduced into the body, some cells will take up that DNA. The DNA then instructs those cells to make the antigen molecules. The cells secrete the antigens and display them on their surfaces. In other words, the bodys own cells become vaccine-making factories, creating the antigens necessary to stimulate the immune system. A DNA vaccine against a microbe would evoke a strong antibody response to the free antigen secreted by cells, and also stimulate a strong cellular response against the microbial antigens displayed on cell surfaces. The DNA vaccine is unable to cause disease