Propaganda

Propaganda: It's here to stay When the word ‘propaganda’ is used, negative connotations are generally brought to mind. People think of politicians using propaganda to force their agenda on others or to slander their opponent’s name as in the new election coming up between Obama and Romney. Yet is this all propaganda really is? Or is there something more that is never discussed about propaganda? This essay will be summarizing and discussing three from Orwell, Lutz , and Woolfolk about propaganda and the English language.The reader will gain a better understanding about what propaganda really is and how it is used and how to avoid getting tricked by it. The first article by George Orwell is out of his book of 50 essays entitled â€Å" Politics and the English Language. † George Orwell is an English journalist and novelist, who wrote such famous books as 1984 and Animal Farm. His article begins by talking about four parts of writing that are misused in the Eng lish language. The first topic discussed is dying metaphors.Orwell says, â€Å"A newly-invented metaphor assists thought by evoking a visual image, while on the other hand a metaphor which is technically â€Å"dead† has in effect reverted to being an ordinary word and can generally be used without loss of vividness. † If someone does not understand a metaphor because it is one that is not used anymore, it loses its effect and should not be used in writing or in propaganda (Orwell). A perfect example is the metaphor of the Hammer and the Anvil. When this metaphor is used most people think it means that the anvil gets the worst of it, when really it is the hammer that always breaks on the anvil.It is a metaphor that has lost meaning because hardly anyone uses an anvil anymore, causing this metaphor to be technically â€Å"dead†. The next subject discussed is verbal false limbs. Orwell says verbal false limbs â€Å"save the trouble of picking out appropriate verbs and nouns, and at the same time pad each sentence with extra syllables which give it an appearance of symmetry. † A few examples Orwell gives include our phrases ‘such as’,’to make contact with’, ‘play a leading part in’, and ‘be subjected to’.The problem is using these phrases takes out simple verbs that give meaning to a sentence and add extra fluff to them in order to sound â€Å"better† (Orwell). When writing it is important to avoid these verbal false limbs so the reader can truly understand what you are trying to say. The third item discussed is pretentious diction. Words such as ‘promote’, ‘constitute’, ‘exploit’, ‘utilize’are used to dress up simple statements and make the person saying them sound dignified. It also is used to add scientific terms to a biased judgment. It is a common trick we see in propaganda all the time.You will see such things as â€Å" It is inevitable if you elect Obama, our country will fail. † The word’ inevitable’ is an example of pretentious diction (Orwell). It is taking a scientific term and adding it to a biased opinion in order to convince the voter that voting for Obama is bad. The fourth item discussed is meaningless words. These are words that are used in which the definition of is unclear. You see this in political ads words such as fascism or socialist. These words are used, but do the readers really know what the author is trying to say by using them. Another one common in political ads is the word ‘patriotic’.Do we have a real definition of what it means to be patriotic or is that a word that is just thrown around. Orwell says that words such as these need to be used carefully and taken out of writing if unneeded. As Orwell ends this article he gives six rules of writing to avoid these crucial mistakes seen in the English language today. The rules are as follows â⠂¬Å"(1) Never use a metaphor, simile or other figure of speech which you are used to seeing in print. (2) Never use a long word where a short one will do. (3) If it is possible to cut a word out, always cut it out. (4) Never use the passive where you can use the active. 5) Never use a foreign phrase, a scientific word or a jargon word if you can think of an everyday English equivalent. (6) Break any of these rules sooner than say anything barbarous. † These rules may seem easy enough but if you grew up writing today it will be harder than you think to change habits and stick to these rules. If you can stick to these rules you will become a better overall writer (Orwell). The second article we will discuss is Doublespeak by William Lutz. William Lutz is an American linguist who specializes in the use of plain words and avoiding doublespeak or deceptive language.Lutz begins talking about how language is a human tool and may be the most important of all the human tools. Yet like any tool, it can be used to build society but can also be used to destroy it (Lutz 25). One quote that Lutz says describes this perfectly, â€Å" Language can easily distort perception and influence behavior and thus be a tool, or weapon, for achieving the greatest good or the greatest evil. † Lutz goes on to talk about how language is power and whoever controls language controls society (Lutz 26). There are four kinds of doublespeak that Lutz talks about the first being euphemism, which is designed to avoid reality.When different words are used to make a situation sound better, this is euphemism. Lutz brings up the subject in 1984 where reports on human rights would remove the word ‘killing’ and replace it with ‘deprivation of life’. This helped the government avoid the subject of government sanctioned killings that happened in other countries that the United States had supported. This is a prime example of doublespeak, using different words to misl ead the reader as to what has really happened. The second type of doublespeak discussed is jargon.Jargon is used all the time by doctors and lawyers; it is speech used that only those in a specialized group can understand. When used in these groups it is not considered jargon because all members understand what is being said. Yet when jargon is used with members outside the group it is then considered doublespeak as all members do not fully understand what is being said (Lutz 27). When companies use lawyer terms to describe something that has happened in their company to the public it is considered doublespeak; they know most people do not understand what they are saying and could use it to cover up what is really happening.The third type of doublespeak that is mentioned is gobbledygook. This is the practice of piling on words, the bigger the better to purposely overwhelm the audience as to what is actually being said. This is common when something bad happens in our economy. Politi cians use big words in long complicated sentences so that their readers do not really know what is going on. The fourth type of doublespeak discussed is inflated language. This is the process of making ordinary words seem fancy and better than what they are.This is often used in advertising to make a product sound better than it is in order to make the audience want to buy it. For example, a used car may be described as experienced (Lutz 27). This is one of the most common ways you see Doublespeak in America today, whether it be in advertising for a product or for a politician. Lutz then discusses how doublespeak is used in politics. â€Å"Political language is the language of public policy and power. Our direction as a nation is defined for us by our elected leaders through language,† says Lutz. Therefore if our leaders are not always honest and pright, we the people do not have the proper knowledge and understanding to make the decisions we need to make. This language has b een distorted in the past such as in Vietnam instead of calling them bombings they called them â€Å"protective reaction strikes. † Orwell said, â€Å"This language is designed to make lies sound truthful and murder respectable, and to give an appearance of solidity to pure wind. † This is why you have a negative reaction when you hear the word propaganda. It's always easier to remember the bad things that have happened and forget the good things (Lutz 29).Not all propaganda is used to mislead or hurt people. It can be used to get people to vote for something that is good and truthful or convince people to recycle. Yet the things that have happened in the past will always give propaganda a bad reputation. The third article is â€Å"Propaganda: How not to be bamboozled† by Donna Woolfork Cross. Donna is an American writer known for such novels as Pope Joan. Woolfork says that propaganda gets a bad reputation because people simply don't understand what it really i s. It is a means of persuasion that can be used for good or evil.Propaganda is used to tell people what toothpaste to buy, the type of movies to see, and the one most people think of, and who you should vote for in an election (Woolfolk Cross 1). Cross says, â€Å"People are bamboozled mainly because they don't recognize propaganda when they see it. † Cross gives thirteen different ways to recognize propaganda. The first is name calling; this is a simple one to understand. It is when someone or group says something bad about another person or group. You see this in political ads all the time or you might hear a politician referred to as â€Å"foolish† or â€Å"fascist†.This is used to make the reader not think but just believe what is being said. Cross then talks about glittering generalities, this is simply the opposite of name calling, it is using terms to make someone look good, it is used to make you want to vote for someone in an election. A political ad ma y say â€Å"Vote for Romney; It's the American way. † This sounds good but when actually examining what they are saying what does it really mean (Woolfolk Cross 2)? The next issue Cross discusses is the plain folks appeal. This is where a politician wants the viewer to think he is a person just like them.A good example is when you see presidents going around to blue collar workers and shaking hands and working with them and kissing babies (Woolfolk Cross 2). They want you to believe that they are the same as you so you will vote for them. Cross also talks about the Argumentum Ad Populum; this is simply telling the people what they want to hear. This can happen in elections as well; you will hear politicians say you all are â€Å"good tax-paying Americans† or â€Å"the backbone of America. † These phrases are things that all people want to hear and our used to distract the voter from what is really being said (Woolfolk Cross 3).The next use of propaganda is the A rgumentum Ad Hominem. Cross says, â€Å"Argumentum ad hominem means â€Å"argument to man† and that's exactly what it is. When a propagandist uses argumentum ad hominem he wants to distract our attention from the issue under consideration with personal attacks on the people being involved. This happens often; if the issue being discussed by a politician is health care reform, then another politician may make an attack about that politician’s bad family life. His bad family life has nothing to do with health care reform, yet things like this will distract potential voters from what is actually being said.The next item discussed is Transfer; (Glory or Guilt By Association) this is simply associating something that is good with the issue at hand even if it has no relevance to that situation. The next propaganda technique is bandwagon. We have all heard the term bandwagon fan to describe someone who likes a certain sports team only because they are doing well. The same ap plies in propaganda; it is used to convince people to like something because it is the popular thing to do (Woolfolk Cross 4). This happens with fashions and is used by getting celebrities to endorse a product.Cross then talks about faulty cause and effect relationship. This is where propaganda says one thing causes another thing to happen even if it really did not. You see this in politics all the time, sense Obama has been in office our unemployment rate has gone down. Now this may be true, but was it caused by Obama or were there other factors in place? It is used to convince people to believe something without actually checking the facts. The next propaganda item discussed is false analogy. An analogy is a comparison between two ideas, events or things (Woolfolk Cross 6).A false analogy is simply comparing two things that really have nothing to do with each other. It is often used in politics to link one thing with another that really has no reason to be associated with the othe r thing. The next propaganda technique, begging the question, this is a common technique used in politics. You may see a political ad that says, â€Å"No true American could turn down proposal 4. † This is forcing the viewer to say do I not want to be a true American (Woolfolk Cross 6). It's basically answering the question for a person instead of letting them answer it for themselves. The 11th item discussed is the two extremes fallacy.This is where you make a situation seem like there are only two options to choose from, either black or white. This forces the viewer to choose one side when really there might be a multitude of options to choose from. The next propaganda technique is card stacking. It's a easy technique of showing only what you want people to see. It's used where politicians only want you to see the good parts of their plans and not the negatives such as raising taxes, they will show you all this great things that will happen but not where the money is coming from (Woolfolk Cross 7). The last propaganda technique is called the testimonial.This is where you get someone who is famous or loved to endorse a certain product or person, even if they are not an expert in the field. You see professional athletes endorsing medical products, even though they are not a medical expert. Woolfolk lays out all thirteen examples of propaganda to show people what to look out for. In conclusion, propaganda is misunderstood. Propaganda itself is not a a negative thing, it is just a means of persuading someone that can be used either for a positive effect or a negative one. Yet in today's society propaganda is used for many different reasons.This is why it is important to understand what propaganda really is. Orwell, Lutz, and Woolfolk give good insight into how propaganda is used and how to avoid being confused by it. After reading this you will have a better understanding of propaganda and how to identify it, and how to understand what the author is reall y trying to say. It will make you a better thinker, and help with important decisions that you have to make. Sources: 1. Lutz, William . â€Å"Doublespeak. †Ã‚  Public Relations Quarterly  . 33. 4 n. page. Web. 2. Orwell, George. â€Å"Fifty Orwell Essays . †Ã‚  Gutenburg. n. page. Web. 13 Sep. 2012.

Importance of Greek Mythology Essay

â€Å"Greek mythology is the body of stories belonging to the ancient Greeks, concerning their gods and heroes, the nature of the world and their own cult and ritual practices. Modern scholars referred to the myths and studied them in an attempt to shed light on the religious and political institutions of ancient Greece and, in general, on the ancient Greek civilization. † (citation) Mythical narration played a very large, and also important role in the lives of the ancient Greeks, they relied mainly on the mythical stories to guide them through crisis and gave them something to believe in; as many people follow God’s words and the Holy Bible in our current time. The epic poems â€Å"The Illiad† and â€Å"The Odyssey† are the oldest known literary sources from the mythology time that we know of. These poems include very many important life lessons such as spiritual growth, loyalty, and perseverance; but these are only a select few of the main themes in the epic poem, â€Å"The Odyssey. † Homer does an excellent job in relating this message through various characters, adventures, and obstacles throughout the book. In the epic poem, â€Å"The Odyssey,† Homer shows the importance of spiritual growth through many instances. Odysseus begins on Calypso’s island and he has been led to believe he owns everything, except for the most important thing, happiness. Odysseus’ becomes depressed because he realizes how much he misses his home land. Homer introduces Odysseus at a bad time to emphasize the growth of Odysseus’ spirit from beginning to the very end. If Homer would have written about Odysseus in high spirits from the beginning, then the growth would not have seemed as prevalent. Odysseus seems to brighten up quite a bit as he sees the light in sailing home. He is brutally tested Poseidon nearly kills him when on the coast of the first island that he reaches, Scheria. The Odyssey says, â€Å"and trapped within that backwash of the brine, Odysseus would have died before his time had not gray-eyed Athena counseled him. † This is only one instance of many that seems to shows the lesson of spiritual growth in â€Å"The Odyssey. † This epic poem also portrays loyalty in very many different ways from characters to situations. In The Odyssey, there remained three main characters that stood out and showed their trustworthiness to Odysseus while he was away fighting in the Trojan War and trying to make his way back to Ithaca. It seems that out of all the characters, the most loyal person to Odysseus could have been simply overlooked, but it most definitely would have been Odysseus’s wife, Penelope. She remained faithful to her husband even after almost twenty years apart from him. She refused to marry one of the suitors that hassled her day by day; so it came as a surprise to learn that Odysseus is most unfaithful to his wife. This part of the epic poem represented the human-like personality of Odysseus in showing that even he could make mistakes, and also wasn’t anything close to perfect. Telemachus, at one point, shows his loyalty to Odysseus by joining him on going on a voyage to learn more about his father, Odysseus. There are a lot of different meanings for each tale and in the Odyssey itself, and there are many more understandings than just one interpretation. From this perspective, one of the main themes of the Odyssey is perseverance. Perseverance is a very important theme and is one that is seen quite a lot throughout the entire epic poem and definitely by more than one character. First of all, there is Odysseus and he was greeted with perseverance in the very beginning of the story. He was held captive by Calypso on an island, when later visited by Athena, Odysseus develops an even stronger desire to go home. In spite of Calypso’s persistence, he then decided to leave. Odysseus also had an encounter with Circe, and was presented with very many different types of temptation. He took the sea once more with his son and wife in mind, and proceeded home. Odysseus and his men end up running into the lotus-eaters. The lotus plants provided an excellent, relaxing feeling for all of the crew, and no one wanted to leave except for Odysseus who stayed his course. Perseverance is also displayed in his way of thoughts, and also his desire to survive and at times conquer, are qualities that promote his perseverance. For example, when Odysseus finally returns home, he plans to kill all of the suitors that have been courting his wife and ends up doing so. Homer’s epic poems The Iliad and The Odyssey have let us get a bit of a taste of the importance Greek Mythology for the ancient Greeks. His writings have let us see how much they believed in the Greek mythology and how they applied the life lessons to their personal lives. I found many comparisons to the Gods and Goddesses of Greek Mythology to our God that many people believe in today. Their words and stories were as important to us as His stories are to us today. Homer’s epic poem, The odyssey included many obviously important life lessons that the ancient Greeks learned from and took from the stories in the way they lived their lives.

The purpose of Building Standards Dissertation

The purpose of Building Standards - Dissertation Example In the UK, over one third of the carbon dioxide emissions come from buildings. The emission of carbon dioxide is very harmful to the environment and in order to protect the ozone layer we have to emphasise the importance of standards. Building Standards are fundamental to the health and safety of us all. In this regard the authorities are working hard to ensure that standards are achieved and continuously improved. Compliance and enforcement has become new issues as standards are being adapted to keep abreast with design, technology, materials and construction, as well as energy conservation issues. However, there has been increasing concerns with regards to the level of compliance, frequency, pace and increasing complexity of these changes. Construction standards have evolved overtime with frequent and more complex Building Regulations since the 1990’s. These changes relate to: Structure of buildings, Fire safety to both dwelling houses and other buildings, Site preparation a nd resistance to contaminants and moisture; Toxic substances; Resistance to the passage of sound; Ventilation; Hygiene; Drainage and waste disposal; Combustion appliances and fuel storage systems; Guidance and Supplementary Information on the UK Implementation of European Standards for Chimneys and Flues; Conservation of fuel and power to existing dwelling houses, other buildings, new dwelling houses and other new buildings; access to and use to buildings; Glazing – safety in relation to impact, opening and cleaning.

The Value Of The Internet For Terrorists - Case Study Al-Qaeda Research Proposal

The Value Of The Internet For Terrorists - Case Study Al-Qaeda - Research Proposal Example With the enormous growth in the size and use of the network, positive aspects of the internet were challenged by the use of the internet by extremist organizations of various kinds. Groups with very different political goals but united in their readiness to employ terrorist tactics started using the network to distribute their propaganda, to communicate with their supporters, to foster public awareness of and sympathy for their causes, and even to execute operations [Weimann, 2004]. The cyber attacks arising from the events of September 11 reflect a growing use of the Internet as a digital battleground [Jenning, 2001]. Since 9/11, public awareness of, and government concern with, Internet security issues has mushroomed. Several news reports and studies have suggested that Al-Qaeda preparations for the terrorist attacks were facilitated by the use of new information and communication technologies, including those associated with the Internet [Deibert, 2006]. FBI Director Robert Muller while addressing the Select Committee on Intelligence of the United States Senate mentioned Cyber-terrorism as a clearly emerging threat. There is cause for uneasiness as the present generation of terrorist groups are found to be increasingly computer savvy, and some probably are acquiring the ability to use cyber attacks to inflict isolated and brief disruptions of U.S. infrastructure. Muller expressed apprehension that as terrorists become more computer savvy, their attack options will only increase [Muller, 2003]. In this context it is particularly important to make an in depth study on the efficacy and use of internet to terrorists groups and to evaluate their way of utilising the cyber world to spread their network and activities, such as for generating support, and networking among their affiliates. Objectives of the study 1. The study will focus on terrorist groups' 'use' of the Internet, in particular the content of the groups' Web sites, and Terrorist groups' use of the Internet for the purpose of inter-group communication and coordination. 2. The possible 'misuse' of the internet by terrorist groups 3. To analyse political agenda or religious fanaticism associated with cyber terrorism 4. To understand the nature and spread of online presence of Al-Qaeda and their gradual and systematic entry into cyberspace.

Overcoming Procrastination. Time Management Article

Overcoming Procrastination. Time Management - Article Example The personal obstacle I faced was procrastination. I had the habit of avoiding doing assignments even when I knew they had to be done. Despite having a highly detailed schedule, I would still find myself procrastinating my duties. This was as a result of getting weighed down by my workload that I would have just put it all off. At most times, I found the lectures so tiring. Concentration was also lacking with new exciting things in this new environment. Some of the causes for poor time management were; lack of self motivation and knowledge as I had no predetermined goals. Maintaining a schedule was difficult due to improper planning for a schedule that was flexible. Procrastination also contributed heavily on managing time as whatever was put off had to be done later at a time planned for another task. To overcome these obstacles, I had to employ some useful tactics. According to my biological tempo and the time of the day it became easy to plan for what would be best to do in the mo rning, day time and evening. I came up with a way to prioritize my day. In the evenings, I would put down most crucial things to be done the next day. I would then attempt them in order of their significance. I would review my progress and fix or adjust my list if necessary. When all significant errands were done, timely and in an organized manner, I would reward myself. For better concentration; studying in particular places like the library is best. Where one can avoid interruption from fellow students or friends, they can cover a lot of work and do their revision. Also switching off the phone or having it in silent mode so as not to get disrupted. During study time, one should only pick urgent calls and shun chatting with friends. Having an arranged working area beats off laziness. One can optimize their working environment. I had a file for all my things and kept them in order of the dates. My class notes were organized and kept ready for quizzes and tests. On a weekly basis, I would conduct a clean up where I would go through all my materials. I filed everything recent systematically and kept old papers in another file at home. Another helpful technique to solve procrastination would be starting on another item after finishing that which you were working on. For example, during study time when done with the day’s work, briefly start on the next assignment so as to be ahead during the subsequent session. If the work is too much you can always do only a small part of the task at a time, and this goes hand in hand with time management. If you do small quantities of the work when it is already nearing the time it should be handed in then the assignment will not be completed, but if one starts doing small portions of the work immediately assigned by submission date, it can be complete and ready to be handed in for marking. A relapse is normal and expected so one must not give up, evaluate what went wrong then try overcoming the obstacles again. After ap plying these techniques, the progress in overcoming my personal and academic challenges was remarkable. Free time and study time were defined clearly after coming up with a flexible schedule. To guarantee success in my studies, there was enough planned study time such that for every hour spent in class two hours would be devoted to revision. I discovered the overpowering problems such as the need for perfection, anxiety and panic and sought them out fast since they are what caused these obstacles in the first place. When the mind is kept occupied at all time, for example, multi tasking it helps. During breaks, going back on what you had studied and revising this for instance definitions covered earlier when studying so that they can be remembered easily if

A Critical Exploration of Roles and Professionalism Essay

A Critical Exploration of Roles and Professionalism - Essay Example Professionalism in this respect and in relation to this paper and that of teaching profession in England shall be taking to encompass teacher’s conduct, their commitment to quality and to learners and upholding of positive attitude. A desirable teacher is the one who assists the learners to learn. The roles undertaken by the teacher require both educational expertise as well as content knowledge. As briefly indicated earlier, the teacher acts as a facilitator, as a role model to the learners, as an information provider, as a leaning resources developer, as a planner and as an assessor. In England the teacher is supposed to pass on information as well as knowledge to the learners. This is presumably the primary role that the teacher plays in facilitating leaning. Here the teacher is expected to share their thoughts in assisting to illuminate the ideas that underlie a certain subject of study. As a role model the teacher should uphold good moral grounds that every learner should emulate. The teacher on the other hand should at all time act as a learning facilitator and a mentor to their learners (Shirley et al. 1984). In England there has been a move towards having a more learner centred learning. Therefore, the teacher has become more of a facilitator in the learning process. The teacher is also taken to be an assessor of learners’ competence. This is where the teacher is supposed to be an excellent examiner who is able to incorporate all the assessment issues. The teacher is supposed to come up with the required learning outcomes as well as assess the learn ers’ leaning outcomes. In the process of assessing the learners’ competence in grasping the content taught, the teacher also assess themselves as the results indicate the effectiveness of the teaching processes applied there before. This encompasses the evaluation role that the teachers should play in instilling knowledge which forms a

Internationa human rights law Essay Example | Topics and Well Written Essays - 1500 words

Internationa human rights law - Essay Example In most cases, the application of extraterritorial jurisdiction statutes often becomes necessary to regulate the conduct of the state agents in another territory if their conducts have an impact on the national interests of their country of origin (Ovey and Robin, 2006, p.25). With regard to international laws, there are cases where extraterritorial jurisdiction has been exercised beyond international boundaries particularly under agreement between the concerned parties or nations. These legal agreements allow the US government to exercise authority and jurisdiction over the members of the US military in these countries. Many other countries have also enacted laws and signed agreements with other countries to allow them prosecute their citizens in other countries for crimes such as genocide, frauds and war crimes among others. This is often practiced regardless of whether the crimes were committed extraterritorially or in their mother countries. For example, the UK government has incorporated the Rome statute act into their domestic laws. This legislation allows criminal cases to be filed against UK nationals who commit crimes in other countries. In this regard, such criminals can be prosecuted according to the standards of the UK laws even if their count ries of residences do not have such laws. Al-Skeini v. U.K was a case involving the investigation of a complaint in which the British troops had allegedly mistreated and killed five Iraqi civilians and maimed the sixth one. Consequently, the families of the victims sought justice from the European Commission on human rights. One of the major controversies surrounding the case was the question of whether the case was within the jurisdiction of the ECHR since crimes were committed outside the United Kingdom. Although the previous jurisprudence had always sought to limit the extraterritorial jurisdiction of the European countries in the other areas they control, the ECtHR Grand Chamber courts ruled that since the

Experience of vendor Essay Example | Topics and Well Written Essays - 500 words

Experience of vendor - Essay Example Being a vendor even with a simple product such as selling lemonade to our community made me appreciate the basic principles of business. One important principle is that my sales must be higher than my expenses. Although most of my supplies came from our kitchen, I still have to think about profit and that my sales should be more than the things that I bought from the grocery such as cups, containers etch. The experience also taught me valuable lesson that it is tough to make money. Customers are fickle and ask a lot of questions even with just a simple lemonade and they could be demanding. As a vendor and seller, I cannot of course complain because customers are always right (I learn that somewhere). We teenagers often do not realize how hard it is to earn money because we just ask it for our parents who in turn has to earn them to provide for the family and that includes us who as a lot of things from then even if many of it are not important. Vending which involves an effort to make money made me realize that money does not grow on trees and it has to be earned sometimes, the hard way. My experience as a vendor selling lemonade and sandwiches to our community may be tough but it has its rewards as well. After the vacation where I did the selling, I saved all my sales and was surprised and happy to have earned that much. I made few hundred dollars and at that time, it was the biggest amount of money that I ever got hold of and it felt good. It felt very good to have that money not because I felt rich but because I earned them by myself. I can still remember when I had that money the things that I can with it. But since I cannot decide, I asked my parents who in turn took the significant portion of it to open a savings account for me and only gave me enough to spend. The reaction of my parents on how to handle my earnings from vending also taught me a valuable lesson to be financially wise. Being financially wise meant not spending all the

Project Management Essay Example | Topics and Well Written Essays - 1500 words - 3

Project Management - Essay Example It cannot it should not be understood the project manager is somehow the be all and end-all of mitigating all problems; however, with regards to the firm or entity in question, they do not have purview over the means by which government bureaucracy or other aspects of the international or regional economy function. Ultimately, they are only capable of directing within their own scope and utilizing their own people as a means of effecting noticeable positive change with respect to the overruns which are to be discussed. It is hypothesized by this researcher that adequate project management within the United Arab Emirates with regards to construction projects has a noticeable effect on the means by which time and cost overruns are realized. Of course the difficulty with regards to this particular research is level and extent to which corresponding research questions can effectively be engaged and answered as a means of drawing inference upon the preceding analysis. As a function of thi s, the following research questions will be asked: What percentage of project managers have prior experience in excess of five years What percentage of project managers exhibit specialized project management training beyond mere higher education What percentage of firms operating within the United Arab Emirates utilize the mastic project managers in order to affect time than monetary constraints To what level to project managers in a given firm integrate with one another within the course of their duties? To shareholders within these companies think favorably or not favorably with regards to project management Naturally, this information will not readily available and must require a questionnaire and/or survey in which affect. Moreover, the research objective be to determine the level to which project management integrates with and positively and/or negatively affects the rate at which cost and time overruns are experienced within construction projects within the United Arab Emirate s. Is the hope of this author that through such an analysis, United Arab Emirates construction industry may experience an increase level of efficiency due to being able to understand the best means of utilization that project management can provide. Similarly, with regards the overall feasibility of the study, it must be understood that this it is only constrained by the level and extent to which the researcher is able to go in order to gain the necessary feedback and input from the stakeholders within the process. If the study is performed to a sufficiently small number of firms and/or stakeholders, the level to which inference can be drawn will necessarily be reduced due to the fact that the results will not be able to shed light upon a broad range of issues and will otherwise really focus upon the means by which if you entities without for sponsoring to the survey/questionnaire. Conversely expanding the survey/questionnaire to include a very large number of respondents will mean that the researcher will spend the majority of time gathering tabulating information without having enough time to sufficiently extrapolate based upon the inputs that are thus far been received. Accordingly, it is the

The Concept of Externalities Essay Example | Topics and Well Written Essays - 1000 words

The Concept of Externalities - Essay Example Among externalities are ecological issues. When ecological issues come in, it is hard to control it. Example for these is the oceans, the rivers, and the air (Gale, 2001). It is hard for a market to cope up especially if there is an ecological exploitation. Most affected to this are those market whose products are taken directly to the one exploited, e.g. like sea foods. But usually the causes of the negative externalities are done also by the market itself. Example are those factory owners, if they dispose there wastes to the streams, they cause pollution. The market maybe aware about the impact they are doing but they think they can get away with it, or because the disposing of the garbage is too high, or they limit the budget for disposing waste to avoid costly method of disposing it (Mind your Business, 2003). In the long run, the negative impact will go back to them and that's when they realize the result of there actions. The market should regulate their waste disposal. They should invest a food was to dispose their wastes. In this case, they can be able to prevent ecological issues. To avoid the market failure, there are things that can be done not only by the market itself but the government can also intervene. Since the market know little about environmental impacts this requires research. This way though causes high costs for research. But there's another way, the government. The government has many accesses to more related action firms about this. The government can enforce an environment-protecting set of standards on the polluting industry. They can also limit the activities of this markets that can cause negative externalities. With this policy, markets will be controlled on their activities that may affect the environment. The government can enforce a tax on the polluter basing on estimated cost the damage done; in return the tax will then be used to eradicate pollution (Thompson, 2005). This way the only affected by the tax imposed are the producers and the consumers of the goods. Quoted from Mind Your Business news (Oct., 2003), "During the summer, they released their annual report - part of which was devoted to reporting on the performance of businesses in relation to incidents of pollution. The report suggests that overall incidents of serious pollution were 20% lower than in 2001 but cautions against any complacency and identifies well known businesses as being guilty of repeat offencesThe average fine per company rose by over one third to 8,744. Fines of more than 20,000 rose by nearly 42% compared to 2001 but the Environment Agency clearly feel that the size of the fines are insufficient to persuade companies to change their behavior. They cite numerous examples of businesses who flouted the regulations including a company director who dumped soil containing arsenic, mercury and cyanide. Arsenic is a deadly poison it its pure form and can cause circulatory problems, skin damage and increases the risk of cancer. Cyanide causes nerve damage and thyroid pr oblems and mercury causes skin disorders, internal bleeding, liver, kidney and intestinal damage. He was jailed for a year!" So for those markets out there beware about the rules and the consequences you might get into when it comes to environmental issues! According to Schultze (2006) that when a market failure occurs the resources fails. He emphasized that

Economic Equilibrium Essay Example for Free

Economic Equilibrium Essay In economic equilibrium, quantity demanded and quantity supplied are equal. For example, the amount of goods or serivices set by buyers is equal to the amount of goods or services produced by sellers. This is what we call as equilibrium price and this will definitely not change unless demand or supply changes. Based on the lecture, due to scarcity we sometimes consider trade-offs. For example as what was stated in the lecture, supposedly that you have only six hours left to study for your test in economics and to complete your assignment in graphic design, you have to balance your time or spend more time in either economics or graphic design. You also have to consider the resources that you can maximize in accomplishing both things. Having a fixed quantity and quality of available resources means that you have a fixed supply of materials such as textbooks, notes, design software, etc. , to use in the time you have left. Scarcity triggers the society to make choices and thats why there are trade-offs. I agree that economic equilibrium is the state wherein you dont get any benefits at all in making trade-offs because there is no tendency to change or you alreay chose the best possible alternative which means that you have maximized already your limited resources. Reference Economics Basics: Demand and Supply. ( 2010 ). Retrieved July 15, 2010 from

What Really Is Actor Network Theory Philosophy Essay

What Really Is Actor Network Theory Philosophy Essay In the 1990s there was a war going on in science, or maybe a few wars the so called Science Wars. From one side there were the postmodernists (better known as post-structuralists), on the other side there were the natural scientists. The war started, or better, culminated with an article, that was really a hoax, published in the journal Social Text, one of the most notorious postmodernist journals. The article/hoax entitled Transgressing the boundaries: Towards a transformative hermeneutics of quantum gravity was written by the physicist Alan Sokal (1996), and its purpose was to show to the world how stupid and meaningless was/is the postmodernist endeavor in the studies of science. The whole article was made up just by meaningless phrases that sounded postmodern (see Sokal 2008 the entire Part I). After the revelation of the hoax Alan Sokal and Jean Bricmont wrote a book entitled Fashionable Nonsense. Postmodern Intellectuals Abuse of Science  [1]   (1998) in which they bombed the whole French post-structuralist scene, and a little bit more. In a nutshell, they showed that most of the French post-structuralists and other close-to-post-structuralism philosophers hadnt had really a clue about science, and that most of their theories come out of ignorance of the fields they were/ are writing about. One of the fashionable guys attacked in Fashionable Nonsense was Bruno Latour (92-99, 124-133  [2]  ), the major representative of Actor-Network Theory (from now on: ANT). He was attacked mainly for pushing extreme social constructivism in social sciences and sciences all together. Basically, Latour supported the thesis that there arent scientific facts but just the social construction of scientific facts as was a fashion of the strong program in the sociology of science  [3]  . Hor instance, he used, no more no less, Einsteins theory of relativity to explain how scientific knowledge is socially constructed, but it seems he didnt really understand Einsteins theory. Latour has lately (2004) changed a little bit his mind about the extreme constructivist positions, maybe because he has seen that his positions really helped not sociology but the political and religious conservative and far right in pushing their ideas about creationism, global warming and similar issues. He even asked himself [w]as [he] wrong to participate in the invention of this field known as science studies? Is it enough to say that we did not really mean what we said? Why does it burn my tongue to say that global warming is a fact whether you like it or not? Why cant I simply say that the argument is closed of for good? (2004:227). This retreat isnt that new. As Gross and Levitt  [4]  noted (1998:59), Latour is aways ready to recast and, in effect, retract what he previously said. In other contexts he will, with an apparently straight face, admit that there is a natural universe out there and that scientific theories are shaped by it in important ways. Simultaneously, he will censure rigorously the dogmatics of strict cultural constructivism. Just as he pictures (literally) the mind-set of science as a Janus-faced dualist, he too is constantly springing from one side of a dichotomy to the other. Bruno Latour, even though he, as we have seen, did repent for the consequences that his and other strong program theorists work provoked, in 2005 wrote an introductory book on ANT: Reassembling the Social. An Introduction to Actor-Network Theory. In that book he tried to explain again the whole ANT story, but not that well, in my opinion  [5]  . In the following lines Ill try to explain, more or less, what ANT is or should be, not just based on the mentioned book, but also on various articles on ANT that can be retrieved on the Internet and other books and journals. ANT seems to be a particular or distinctive approach to social theory and research which has its origins in the field of Science and Technology Studies (STS), mostly developed by Michel Callon, Bruno Latour and John Law. In the last twenty years ANT has been used as a tool for research in fields such as organizational analysis (for ex. Cochoy 2009), informatics (for ex. McInerney 2009), health studies (for ex. Dent 2003), geography (for ex. Smith 2003), sociology, anthropology, feminist studies and economics (for ex. Jones 2008). Already the title of the theory is very problematic. Bruno Latour states in his book (2005:9) that [] the historical name is actor-network-theory, a name that is so awkward, so confusing, so meaningless that it deserves to be kept. Every part of the ANT is questionable. Its not really about actors in a classic sociological sense, the network part is misleading (see Latour 1998) because it doesnt refer to the concept of network as in Social Network Analysis or electronic networks  [6]  , and it is not really a theory in the classic sense, it can be reckoned as a set of theories which have similar characteristics. As a matter of fact, he admits that he was ready to drop this label for more elaborate ones like sociology of translation, actant-rhyzome ontology, sociology of innovation, and so on []. (2005:9). How then we can recognize a theory that belongs to the ANT family? Latour puts forward three tests in order to do that (2005:10-11): One of them is the precise role granted to nonhumans. They have to be actors [] and not simply the hapless bearers of symbolic projection. [] [A]ny study that gives non-humans a type of agency that is more open than the traditional natural causality but more efficient than the symbolic one can be part of [ANT] corpus, even though some authors would not wish to be associated in any way with this approach.(10). Another test is to check which direction the explanation is going in. [] If the social remains stable and is used to explain a state of affairs, its not ANT. (10) A third and more difficult test would be to check whether a study aims at reassembling the social or still insists on dispersion and deconstruction. [] Dispersion, destruction, and reconstruction are not the goals to be achieved [as in postmodern theories,] but what needs to be overcome. Its much more important to check what are the new institutions, procedures, and concepts able to collect and reconnect the social []. (11). We can see that Latour is very vague, and it seems he wants to be like that. In short we can say that in ANT humans, nonhumans and language are all on the same level. They all together form a network of actors that form the world. He uses and criticizes very often the concept social, many times as opposed to the concept associations. Social is for him a concept that many sociologists use as a name for a material the society is made of (2005:1), or some glue of society. But thats wrong, because there isnt something social, there are associations between heterogeneous elements (2005:5). Thus, social, for ANT, is the name of a type of momentary association which is characterized by the way it gathers together into new shapes. (2005:65). In my opinion this is not that groundbreaking. Well, the association of humans and nonhumans might be a little bit strange (or Im too positivist and backwarded), but the idea of not using concepts as social forces and similar black magic (or as Latour wo uld call, as we shell see, black boxes) terms is present in sociology much longer than ANT. For example we can check Howard S. Becker (2007) where he explains the errors of using vague concepts as social forces, etc So, interactionists (try to) explain already very well what people do and how they create everyday life, without going into exotic theories that are not that clear even to their main representatives. ANT is considered sometimes a method and sometimes a theory. [A]nti-essentialism informs both the conceptual frame used for interpretation and guides the processes through which networks are examined. (Ritzer 2004:2). There are three methodological principles in ANT: agnosticism. We should abandon any a priori assumptions of the nature of networks, causal conditions, or the accuracy of actants accounts (Ritzer 2004:2). There should be impartiality from our side. This principle reminds us about Grounded Theory methodology with the added value of impartiality towards objects that are not humans. generalized symmetry. Everybody in a network is the same: computers and programmers, clerks and computer networks Basically we should dissect everything free association. there shouldnt be any distinction between natural and social phenomena. The ANT methodology is usually ethnographic. To be precise they often use the case study method. They use to spend time like anthropologists, but not in forests, and other places typical for anthropological research, but in laboratories with scientists. ANT scholars also study inscriptions, a phrase which refers to all texts and communications in all media (Garson 2008). Let us see which are the central concepts of ANT. I will use secondary analyses of ANT by Felix Stalder and David Garson. Here are the main concepts: Actors: entities that do things (Latour, 1992a, p. 241, as cited in Stalder 1998), no matter whether they are humans or any kind of nonhumans. Some authors use actors for humans and actants for other parts/ system elements of the network (Garson 2008)  [7]  . The distinction between humans and non-humans, embodied or disembodied skills, impersonation or machination, are less interesting than the complete chain along which competences and actions are distributed. (Latour, 1992a, p.243, as cited in Stalder 1998) [] An actor is an actant endowed with a character. (Akrich, Latour, 1992, p.259 as cited by Stalder). In Ritzer (2004:1) we can find that [t]he volitional actor for ANT, termed actant, is any agent, collective or individual, that can associate or disassociate with other agents. Actants enter into networked associations, which in turn define them, name them, and provide them with substance, action, intention, and subjectivity. In other words, actants are considered foundationally indeterminate, with no a priori substance or essence, and it is via the networks in which they associate that actants derive their nature. Network: the network is defined as a group of unspecified relationships among entities of which the nature itself is undetermined. (Callon, 1993, p.263 as cited in Stalder 1998). The inclusive character of this definition becomes more evident when contrasted with one of the conventional sociological definitions of network where a social network consists of a finite set or sets of actors and the relation or relations defined on them (Wasserman, Faust, 1994, p.20 as cited in Stalder). An actor-network is not restricted to social actors, not even to actors in the theorys broader sense. There is no structural difference between large and small actors, between a major institution or a single individual or even a thing as mundane as a door opener (Latour, 1992 as cited by Stalder 1998). Black Box: simply put, a black box contains a sealed network of people and things. But lets see what ANTers say: A black box contains that which no longer needs to be considered, those things whose contents have become a matter of indifference. (Callon, Latour, 1981 p.285 as cited in Stalder 1998). A black box, therefore, is any setting that, no matter how complex it is or how contested its history has been, is now so stable and certain that it can be treated as a fact where only the input and output counts. (Stalder 1998). For example, all the concepts in sociology as social forces, etc are black boxes. Cars are black boxes because we can drive them even though we dont know how are they built. The more it costs to reopen a black box, the more it will be stable. Its not just a matter of the black box, but also of the environment in which it is settled (well, everything is in the network). At the end of the day it seems that ANT became a black box too, because it became a fixed center or obligatory point of passage by the mid-1990s (Ritzer 2004:3). Other important concepts are: Punctualisation: a concept that means that the whole actor-network is greater than the sum of its constituent parts. As networks build, synergistic capabilities are enabled; as networks fall apart, de-punctualisation refers to the collapse of networked capabilities as individual components struggle to pursue their individual goals separately. (Garson 2008). Tokens: are the quasi-objects created through the synergy of network punctualisation. (Garson 2008). The constant creation of tokens reifies a network, when they stop being reproduced the network breaks down, or, there is de-punctualization. Translation: is the process of forming a network. This process occurs in the four following moments or steps (Garson 2008): Problematisation: defines the problem and the set of relevant actors who become indispensable Interessement: primary actor(s) recruit other actors to assume roles in the network, roles which recognize the centrality of the primary actors own role Enrolment: roles are defined and actors formally accept and take on these roles Mobilisation: primary actors assume a spokesperson role for passive network actors (agents) and seek to mobilize them to action. Translation is really a negotiation among human actors and representatives of material actants. Stories: The complex process of translation which forms a network also occasions some actors to emerge as spokespersons, articulating the views and wishes of other silent actors in the network. Negotiation in the translation process is marked by: Obligatory points of passage (OPP): they are critical network channels often designed by the primary actor to ensure that communication must pass through his or her domain. In this way the actor becomes functionally indispensable to the network Cooptation: it is a subprocess by which actants seek to have their individual objectives become agreed to by other actants as part of defining network objectives. Actors advance favored goals and solutions, then recruit other actors to be allies in the process of forming commitments to emerging networks. (Garson 2008). Translation model of power: it is a term for viewing power as a relation emerging bottom-up rather than imposed top-down. Those who hold power in principle may not hold power in practice as the latter requires the ability to define, create, and stabilize networks of actors motivated to work in conjunction to accomplish a task. That is, power is seen as a consequence of convincing, enrolling, and other network-building activities. (Garson 2008). This concept reminds a lot the foucaultian concept of microphysics of power. Black-boxing: it is a subprocess by which the network becomes more simple by treating subnetworks as single elements in an actor-network Irreversibility: is achieved by an actor-network when it is no longer possible to return to an earlier network state or to alternatives present prior to the network Network instability. Actor-networks are in a continual state of becoming, including possible dissolution. Networks demand continual maintenance or order In my opinion all the concepts are vague, probably intentionally. I really wonder if the whole theory and its concepts could have been explained in a more simple way, and I wonder why is it always like that in post-structuralism (I know, this is an ad hominem mistake)? ANT was often criticized for being managerialist, for emphasizing Nietzschean mastery, as Machiavellian, for colonizing the other, for being antihumanist, and for representing the powerful. (Ritzer 2004:3). I would add that the founders of ANT write pretty much in an elitist and unclear way. It sounds more like poetry or showing off with strange PoMo-style phrases difficult to understand. I got used to that with Baudrillard, Lyotard, etc But what can we do with it in everyday life? We cannot stop natural scientists to laugh about ANT mumbojumbo for sure. I would say that ANT as a research methodology brings nothing new, or nothing newer than the good old methodology of case study, the grounded theory methodology (Glaser/Strauss 2008) or ethnomethodology on which ANT is partially based. As an explanation for what is really going on it is still a safe bet to stick with interactionist theories from one side, and on the other side, we should use more explanatory theories based on strict field research and model building. For that is handy the analytical sociology approach developed, among others, by Peter Hedstroem (see Hedstroem 2005). With the analytical sociology approach we could finally develop more core knowledge which is feeble in sociology (see Cole 1994) but nevertheless it exists (see Collins 1989) and leave the research frontier to a few artists. Analytical sociology seeks to explain complex social processes by carefuly dissecting them and then bringing into focus their most important costituent components. [] It is an approach that seeks precise, abstract, realistic and action-based explanations for various social phenomena. (Hedstroem 2005:1). So, in the analytical approach we have to explain social phenomena, not just describe it as most grand social theories do. We have to dissect the social phenomena to its smallest parts and then abstract the most important parts and build a model. In doing that we must be precise and clear. If it is not perfectly clear what a given theory or theorist is trying to say, how can we then possibly understand and assess the potential merits of the theory being proposed ? (Hedstroem 2005:3-4), asks Peter Hedstroem, and as an example of unclear theory he takes a French (who else could he take?!) sociologist Pierre Bourdieu and his definition of habitus (2005:4). I agree with Hedstrom that social theories should be based on the construction of models, or explaining social mechanisms, and a social mechanism is a constellation of entities and activities that are linked to one another in such a way that they regularly bring about a particular type of outcome (Hedstroem 2005:10). To conclude, I think that ANT is maybe an approach that could have a major success in the future when there will come the time people will understand French philosophy much better  [8]  , until then I propose to stick with more positivist approaches that can actually really explain why things happen.

Analysis of SAMe as an Antidepressant

Analysis of SAMe as an Antidepressant S-Adenosyl-Methionine (SAMe) And Improved Methylation Offer A Serious Alternative To Orthodox Medications Can S-Adenosyl-Methionine (SAMe) and improved methylation offer a serious alternative to orthodox medications in the treatment of depression? Abstract In this dissertation we consider the issues surrounding the use of SAMe as an antidepressant. There are many different aspects to this consideration. We start by a consideration of exactly what depression is on a clinical basis and examine the psychological and physiological changes that characterise the condition. We then consider and examine the evolution of the current forms of antidepressant medication. We explore the fields of neurochemistry and pathophysiology of depressive states with particular emphasis on the chemistry of the methylation reaction and its relevance to the SAMe compound. Consideration is then given to SAMe specifically as a medication and the evidence that there is to support its apparent beneficial effect in depression. This is then expanded with a review of the chemistry of SAMe and its interactions with other biologically active entities. We conclude the exploration with a critical review of the published literature that is relevant to the role of SAMe as an antidepressant agent. Introduction In order to investigate the full extent of the question at the heart of this dissertation we must examine a number of background issues in some detail first. Depression is a complex clinical state. It has been said that there are as many theories about the aetiology and treatments for depression as there are clinicians thinking about the problem. (LeDoux, J. 1996). A brief examination of the literature on the subject tells us that this comment, although clearly intended to be flippant, may not actually be so very far from the truth. Perhaps it is because of the plethora of hypotheses, ideas and theories on the issue that there are also a considerable number of forms of treatment that are commonly employed. It has to be admitted that some are rational and some appear to be completely irrational. In this dissertation we shall examine some of the more rational forms of psychopharmacology in order to understand the place of SAMe in the therapeutic pharmacopoeia. Depression is a commonly occurring illness. It will significantly affect between 10-25% of women and approximately half that number of men during their lifetimes. Approximately 5 million people in the UK will experience significant depression in any given year. (Breggin 1994) If you suffer from an acute or chronic illness you are even more likely to suffer from depressive states with frequencies ranging from 30-50% depending upon the nature and severity of the illness. (Robertson et al 1997) What is depression ? There are many definitions of clinical depression and indeed many different rating scales which purport to try to quantify it. It is important to distinguish between clinical depression and simply feeling down or miserable. Depressive illness typically occurs in episodes although in some cases it can actually last for many months or even years. (Skolnick, P. 1999). One severe depressive episode is a major independent risk factor for getting further episodes. In other words, having had depression once you are statistically considerably more likely to have another attack. (Post RM. 1992). For our purposes we shall consider a practical overview of the nine classic symptoms that characterise classical depression 1. Depressed mood for most of the day 2. Disturbed appetite or change in weight 3. Disturbed sleep 4. Psychomotor retardation or agitation 5. Loss of interest in previously pleasurable activities; inability to enjoy usual hobbies or activities 6. Fatigue or loss of energy 7. Feelings of worthlessness; excessive and/or inappropriate guilt 8. Difficulty in concentrating or thinking clearly 9. Morbid or suicidal thoughts or actions. (After Zuess 2003) The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) states that in order to merit a diagnosis of clinical depression you need to demonstrate at least five of these symptoms and that they represent a change in your life. Mood alterations are commonplace in depressive states. The depressed patient will classically feel despair or sadness. Pleasure becomes an alien emotion as they tend to progressively loose interest in activities that they would have previously enjoyed. Mood swings can also occur although they are more commonly found in bipolar states (manic depression). Subjective feelings of tension or irritability are often described as well as just sadness. (Duman et al 1997) In addition to mood changes, depression can also produce changes in the emotional state as well. Feelings of worthlessness and guilt are perhaps the commonest emotions in the clinical spectrum. This is closely followed by both ineptitude and lack of confidence in ones own abilities or capabilities. It is common for depressed people to take action that avoids them having to take responsibility because of an overwhelming fear of failure. (Altar CA 1999) Somatic manifestations of depression are perhaps easier to quantify as they have a qualitative characteristic about them as opposed to the purely subjective. Changes in appetite are commonly found. Generally it is an anorexic change with a decrease in appetite and a loss of interest in food generally. Less frequently, the converse is observed with a voracious increase in appetite (comfort eating) which is normally associated with weight gain. This weight gain can be quite substantial in extreme cases. Sleep disturbances are commonplace. Insomnia and early waking are perhaps the commonest of this type of symptom. This can occur despite severe subjective symptoms of somatic tiredness and fatigue. Some people will find that fatigue is a prominent symptom and may find that this is translated into excessive sleeping and motor retardation generally. Fatigue is actually more difficult to quantify, but it is commonly experienced by the depressed patient. It can either be an overwhelming tiredness (lack of energy) or perhaps lack of stamina (tiring too easily). Associated with this is often a reduction in libido and, if severe, impotence can also occur. It is not unusual to find sexual avoidance behaviours developing in these circumstances. (Janicak et al 1989) Concentration is commonly impaired. Generally speaking the greater the degree of depression, the greater is the degree of concentration impairment. Thinking and reasoning processes slow down and the attention span is often markedly reduced. Students find they can have an inability to study and if severe, patients report an inability to even sit and watch television. (Bazin et al 1994) Somatic symptoms can occur without the psychological elements of the depression being apparent or obvious. This is a common clinical dilemma. Patients may enter a phase of denial or minimisation where they will not accept that they are actually depressed. They can try to rationalise their physical symptomatology into other disease processes. This can be mistaken for hypochondriasis. (De Vanna et al 1992) If depression is severe (or occasionally part of a symptom complex of another underlying pathology), then psychosis can be found. Delusional states are not uncommon in severe depression. Hallucinations can occur, but they are comparatively unusual. Patients can state that they hear voices telling them that they are worthless or perhaps instructing them to kill themselves. Although this is consistent with a depressive diagnosis, one should note that other illnesses such as schizophrenia must clearly be considered and excluded before a confident diagnosis of depression can be made. The actual basis or specific triggering factors for depression are not yet clearly defined but we do know that a number of different biological factors are relevant. Environmental factors, together with both genetic and neurobiological elements are all capable of influencing the overall clinical picture. (Kendler KS, 1998). Depression is broadly divided into endogenous and reactive types. In general terms endogenous depression is thought to be influenced the genetic and neurobiological factors whereas reactive depression may well have environmental factors as being relevant. This has considerable implications in our considerations of the possible actions of SAMe. (Gold et al 1988) Pharmacology of depression This is a vast subject and is generally considered to be a sub-speciality in its own right. It has long been recognised that certain substances appear to be able to exert a mood elevating effect. The advent of modern psychopharmacology allowed us to develop an understanding into just how some of these substances work. The drugs and medicines that are in common use today are the result of a process of evolution that, arguably, began with the uses of herbs at the beginning of recorded history and progressed to the chemically and biologically sophisticated compounds that are in use today. (Peinell and Smith 2003) In order to put the SAMe compounds into their appropriate place in the continuum we need to look at some of the evolutionary developments in the field. Most of the currently used antidepressants work by interfering in some way with the actions of the various neurotransmitters in the brain. Many work by slowing down the biological processes of degradation or destruction of these neurotransmitters. In purely simplistic terms, this results in a greater concentration of the neurotransmitter at the critical synaptic interfaces within the brain. (Levine et al 1998) The first real breakthrough with what could be considered to be a major therapeutic agent for depressive states came with the discovery of the MAOI (Monoamine Oxidse Inhibitors), group of drugs. Three were commonly used in clinical practice isocarboxazid, phemelzine and tranlcypromine. For a while they were used extensively but it became obvious that they had serious drawbacks including some potentially fatal side effects. (Saarelainen et al 2003), Headaches dizziness and tremor were not unusual accompaniments of the drug. They also had the ability to interact with other medications and certain types of food (tyrosine containing foods such as cheese could cause hypertensive crises). Despite these drawbacks, many patients were willing to take them because they indisputably worked. (Skolnick 1999) In time, the MAOis were superseded by the Tricyclic group of drugs. There were four in common use, namely amitriptyline, desipramine, imipramine and nortriptyline. These were generally speaking, marginally more effective than the MAOIs but they were without the worst of the side effects. Despite that, they were still able to cause dry mouth and blurred vision in some people. Constipation and drowsiness were not unusual and they were not commonly used if a person also had hypertension. The pharmaceutical industry then produced a number of different categories of medication in fairly quick succession. SSRIs (Selective Serotonin Reuptake Inhibitors), SNRIs (Serotonin and norepinephrine reuptake inhibitors) and NDRIs (Norepinephrine and dopamine reuptake inhibitors) all emerged into the market place. (Smith et al 2004) It is probably fair to say that they all had their niches in the therapeutic spectrum but the SSRIs were seen to corner the biggest share of the clinical market with citalopram, escitalopram, fluoxetine, paroxetine and sertraline as examples of the group. Fluoxetine was probably the most widely used and its trade name, Prozac was accepted almost as a household word. The side effect profile of this particular group was certainly less significant than their predecessors, but nausea and headaches were not uncommon. (Stewart et al 2000), The SNRIs fell into disuse largely because of their reputation in raising cholesterol levels and the NDRIs were found to cause unacceptable agitation in certain groups. There was then an emergence of a group of drugs which not only blocked the mechanisms that removed the trophic neurotransmitters from the synapse they also had an effect which effectively enhanced their action by blocking the action of the inhibitory neurotransmitters at the same time. There are several types of medication in this category, but perhaps the best known is maprotilene. Like most of the other types of effective medication, it is not without side effects. Drowsiness, nausea, dizziness and a dry mouth are common accompanying symptoms of a therapeutic dose of this medication. (Harmer et al 2003) Neurochemistry and pathophysiology of depression So far we have take a brief and admittedly comparatively simplistic tour of the nature and pharmacology of depression. We shall now look at the neurochemistry and pathophysiology of certain relevant aspects of the subject in more detail. In general terms, stress and antidepressants appear to have reciprocal actions on neuronal growth and to some extent, on their activity (see on). This appears to be through the mediation of various neurotrophins and the action of synaptic plasticity mainly in the region of the hippocampus and some other brain structures (Reid et al 2001). Various stresses appear to disturb and disrupt the activity, both of individual neurones and also larger functional groups, or networks of neurones whereas antidepressants appear to antagonise this disruptive ability. (Henke 1990) There is a large body of opinion which agrees with the hypothesis that regulation of synaptic activity is a major key to the pathophysiology of depression and related disorders. (Drevets et al 1997) The discovery of the MAOI group of drugs (above) led researchers to speculate that the monoamine group of neurotransmitters were central to the aetiology of depression. As more research is done it is becoming apparent that this may not actually be the case. It is now considered more likely that the fundamental problems lie further along the metabolic cascade from the monoamine oxidase activity. It is also considered likely that the pathology may well not be just a chemical imbalance, but may well involve other functions of neural tissue such as various cellular changes in physiology, genetic factors and the ability of neuronal network to change their characteristics. (Czyrak et al 1992) Observational studies have suggested that early life experiences, the impact of stress and the presence or absence of social support or interactions all have an influence on the development of a depressive state. (Gould et al 1998).Consideration of the monoamine chemistry clearly does not account for all of these factors although it is clearly acknowledged that it does play an important contributory role. Some recent work relating to the chronic use of different classes of antidepressants (Duman et al 1997), has appeared to show that they all are able to increase the production of the neuroprotective groups of proteins which, amongst other actions, play a central role in the plasticity of neurones. Current thinking is that this may well be a common function of a number of different pathways that the different antidepressants exploit. It is known that increases in monoamine levels in the synaptic region result (by a number of different mechanisms) and are associated with the induction of enzyme systems that control gene expression within the neurone. This can be inferred from the finding of increases in the levels of messenger RNA which codes for the cAMP response element binding protein (CREB). These levels slowly increase with chronicity of administration of antidepressants and this mechanism may well account therefore for the commonly observed slow and progressive onset of action of most of the antidepressant drugs. It is proposed that CREB triggers the production of BDNF (Brain Derived Neurotrophic Factor). This is significant since other work has shown that stress antagonises the levels of BDNF which is opposed by the actions of the antidepressant drugs. (Smith et al 1995). Further credence is given to this theory with the discovery that placing BDNF directly into the brain of experimental animals appeared to relieve many of the behaviour patterns that are associated with depression (Siuciak et al 1997) Some authors have suggested that depression may represent a particularly subtle form of neural degenerative disorder as it has been shown that the hippocampus becomes progressively atrophic in chronic depressive states. This is particularly significant as BDNF is thought to reverse such findings. (Shah et al 1998). There is associated supporting evidence in the form of a study by Vaidya (et al 1999) which shows that ECT treatment (which was always assumed to be detrimental to the neural structure and physiology) is associated with both increased levels of BDNF and trophic changes in the hippocampal neurones. A paper by Czyrak (et al 1992) looked at the antidepressant activity of SAMe in mice and rats in a way that clearly is not possible in humans. It is not always possible to directly extrapolate findings from animals to humans, but there are some pieces of evidence in this work which strongly implicate SAMe in the pathogenesis of depression. The paper itself is extremely long and complex but the relevant parts to our considerations here are the fact that normal geographical exploratory behaviour in rodents tends to diminish if a depressive state is induced. To some extent, exploratory behaviour is therefore considered a marker for the depressive state. It was found that SAMe tended to increase exploratory activity in mice. This, and other more sophisticated testing of the pharmacological interactions of SAMe showed that it tended to have the same psychopharmacological profile as many of the mainstream antidepressants. Many of the neurotransmitters and for that matter some neuroactive hormones have been variously implicated in the aetiology of depression (eg thyroid hormones and noradrenaline). (Nemeroff, 1998). Modern research has most consistently found that alterations in the levels of serotonin (5-HT) (Melzter H, 1989), system and the chemicals of the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis. (Kathol et al 1989), as the most consistently implicated mechanisms that appear to be associated with the control of the mood stabilising and regulating mechanisms. It is in fact very likely that both these mechanisms are in some way interlinked as part of the regulatory mechanism of mood. We have already referred to the role of stress in the aetiology of depression. We know that the adrenal glucocorticoid hormones subtly interact with the 5-HT system and these are produced in direct response to stress. (Lopez et al 1999) (I). We also know that the glucocorticoids have a number of direct effects on the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis. It may be that this is the mechanism by which stress antagonises the changes brought about by SAMe. (Lopez et al 1999) (II) We do not need to consider the effects of the corticoids on the LHPA axis in detail as it is only of peripheral relevance to our considerations here. The important consideration in this regard is that the LHPA axis is intimately connected to the hippocampus. It is this structure that is the intermediate step and connection between the bodys hormonal response to stress and the response of the higher functions of the brain. (Dallman et al 1987). The immediate relevance of all this to the actions of SAMe are that hyperactivity of both the hippocampus and the LHPA axis are both well documented in cases of clinical depression. This has been shown to also be associated with high levels of corticosteroid production (Kalin et al 1987), but one study has shown that in suicide cases who have had profound depression the hippocampus has fewer corticosteroid receptor sites than one might normally expect (Lopez et al 1998). One further piece of clinical evidence in the role of the corticosteroids in depression is that patients with Cushings disease have a high incidence of depression. This incidence returns to normal when their hormonal over-activity is treated and returned back to physiological levels. (Murphy 1991) SAMe as a medication SAMe was discovered in Italy in 1952 during research into the chemistry of neurotransmitters. It was not, however, introduced in a useable form for patient benefit until 1974 (as SAMe sulphate-paratoluene-sulphonate). It is for this reason that the majority of the early papers and work on the subject are almost exclusively Italian in origin. (De Vanna et al 1992) SAMe has been used clinically in a number of conditions including cholestasis, osteoarthritis and depression. (Carney et al 1987) Although there is a wealth of literature on the first two elements it is not relevant to our considerations here. We shall therefore restrict this discussion to the spectrum of its use in the field of depression. A number of studies have shown that SAMe has useful activity in depressive illness. Studies that have compared it to placebo have found that it can consistently produce about a 6 point increase on the Hamilton rating scale after about three weeks of optimum treatment. This finding is approximately in line with the results that are found with most of the other clinically effective antidepressant medications. (Cooper et al 1999) (De Vanna et al 1992) Some studies have found that using SAMe in a large dose has produced an unusually rapid onset of beneficial effects (Kagan 1990) One could argue that, because it is a naturally occurring substance, it would not be likely to have a high side-effect profile. Although these two statements do not always follow, it is generally true. A study by Bressa (1994) on the issue showed that it did have a particularly low side-effect profile, particularly when compared to the other antidepressants (Tricyclics). To demonstrate this point further, we can point to the study by Caruso (et al 1987) where there were a greater number of patient withdrawals due to the side effects of the placebo than withdrew because of the SAMe drug. For the record, that particular trial was in its use as an antiarthritic rather than an antidepressant, but the point is made. The two major unwanted clinical effects are nausea and hypomania. The nausea is not a local effect on the gut lining but appears to be a centrally mediated effect and is possibly caused by the same phenomenon of over-stimulation of the neuronal networks which causes the other major clinical manifestation of hypomania. For this reason it is generally not used in cases of bipolar disorder. (De Vanna et al 1992) It is probably not strictly accurate to refer to SAMe as a drug as it is normally found in the cellular matrix. It has been found to be effective in patients who have been unable to tolerate other forms of antidepressants or, for that matter, have had minimal response to them. (Reynolds et al, 1984) Young (1993) produced a particularly interesting review of dietary treatments for depression. A lot of his article is not relevant to our considerations here, but he makes a number of interesting and relevant observations. Low serotonin levels are known to be associated with depression even though low levels on their own do not appear to cause the condition. It appears that it needs to be in combination with a low level of folic acid. We know that low levels of folic acid are also often found in combination with depressive illness and that low levels of folate are often associated with low levels of SAMe. The evidence points to the fact that the low levels of serotonin are more likely to be a result of the low SAMe levels in neural tissue and that this is more likely to be nearer to the root of the main anomaly that causes depression. Pregnancy is known to be associated with low levels of folate and post natal depression is a well recognised clinical entity. Salmaggi (et al 1993) considered the effects of SAMe in the postnatal period. This was a well considered and constructed study. It was a double blind placebo controlled trial over a 30 day period and had an entry cohort of 80 women. The degree of depression was assessed before, during and after the trial on the Hamilton Scale. The results showed a statistically significant improvement in the SAMe group when compared to the placebo group. The authors comment that there were no significant side effects of the medication encountered. Because we know that any beneficial effect that SAMe is likely to have on a patient tends to be seen more quickly than with the other antidepressants, and also, by virtue of what we suspect about its probable mode of action in the hippocampus and elsewhere in the brain, it seems a logical step for someone to look into the effects of giving SAMe alongside a conventional antidepressants to see if there is either any synergistic effect or possibly a speeding up of the clinical onset of the secondary medication. The study by Berlanga (et al 1992) did exactly that. Unfortunately the trial was not particularly rigorous in its design as although it was double blind, it was not placebo controlled, which would appear to have been the method of choice in this type of investigation. Its other problem as that it only had an entry cohort of 40 patients. Despite these limitations it was indeed shown that depressed patients who took SAMe in conjunction with other antidepressant medication found that the depressive symptoms resolved faster with the SAMe added to their normal treatment regime. There are one or two other less important papers which we shall only mention in passing. Kagan (et al 1990) ran a small trial on 15 inpatients (with very severe depression) and found SAMe to be a safe, effective antidepressant with few side effects and a rapid onset of action. This particular trial is notable as it was the first to report the side effect of mania in a patient who didnt have a previous history. Another is the trial by Rosenbaum (et al 1990). This particular trial is notable for the demonstration of the fact that about 20% of other treatment resistant patients experienced benefit with SAMe. Faya (et al 1990) (II) considered the fact that SAMe is thought to exert its effect through its action in increasing dopamine levels in the synaptic cleft. It is known that dopamine inhibits the production of both Thyroid stimulating hormone (TSH) and Prolactin from the pituitary gland. Faya considered measuring the levels of both TSH and Prolactin during treatment with SAMe. His findings constituted something of a surprise insofar as in the men in the trial group had their levels of TSH and Prolactin reduced which is consistent with the hypothesis that SAMe increases the dopamine levels in the brain. Much to everybodys surprise, this effect was not seen in the female group. The authors do not offer any explanation of this fact. For the record, there is another trial (Thomas et al 1987), which obviously considered the same phenomenon and their trial did not show any sex linked difference in the suppression of the Prolactin levels With regards to efficacy, a trial by Carney (et al 1986) suggests that the beneficial action of SAMe is restricted to endogenous depression and it does not appear to have any action above placebo on reactive depression. As far as we can ascertain, this is the only trial published that has made this suggestion, although from a first principles basis, one can see the biochemical rationale for believing that it might well be the case. On a purely empirical grounds, some authors have recommended (on the basis of scant hard evidence), that SAMes action can be maximised by the addition of B12, B6 and folic acid. It is known that SAMe is required to convert these agents into their active form as a coenzyme. (Morrison et al, 1996). The same author also recommends the simultaneous adminstration of Trimethylglycine (TMG) which is necessary for the intracellular conversion of methionine into SAMe by the provision of the necessary methyl- groups. Comment has to be made that again, this appears to be a completely empirical (and logical) suggestion, but we cannot find any hard evidence to substantiate its clinical use. Chemistry SAMe is a basic component of cellular biochemistry. It occurs in every living cell and is second in importance only to ATP in both the number variety and significance of the reactions in which it serves as a cofactor. (Stramentinoli 1987). It is central in the chemistry of the transmethylation reactions. In essence its cellular function is to transfer the active methyl group form carrier molecules to a multitude of other molecules. In general terms, this methylation makes inert molecules biologically active. In addition to the transmethylation reactions it also plays a central role in transsulfuration and aminopropylation reactions It is involved in the synthesis of proteins including the nucleic acids, fatty acids, lipids and phospholipids, porphyrins and polysaccharides. In terms of our considerations here, perhaps the most significant reaction type that SAMe is involved in is the generation of the neurotransmitter amines. In this regard it is considered to be the most biologically significant provider of methyl groups within the cell. (Baldessarini 1987). Significantly it is also involved in the pathways to produce a number of other neurologically active compounds such as adrenaline, the neuronutrients acetyl l-carnitine and phosphatidyl choline (Mathews et al 1990) It is also to be found in the metabolic pathways of both serotonin and dopamine. Oral administration has been shown to increase the metabolites of these compounds in the CSF (implying increased turnover). It is thought to exert its antidepressive effect partly through the mechanism of increasing the levels of both dopamine and serotonin as neurotransmitters, but it also appears to have some form of trophic action on some of the neurones in the brain cortex. (Baldessarini 1987) It has been demonstrated that the tissue levels of SAMe tend to diminish with age and blood levels are also found to be low in some cases of clinical depression (Baldessarini 1987) A methyl group (CH3) is a group of three hydrogen atoms bound to one carbon atom. It does not exist in a stable isolated form and is transported between molecules by intermediaries such as SAMe. Methylation is the process by which this group is transferred from the methyl donor molecule to the recipient molecule. In general terms this process is central to the control of many of the intracellular pathways. Giving a methyl group to an enzyme is often the key to activating it, and thereby beginning a synthesis or degradation process elsewhere in the cell. Equally removing the methyl group will render the enzyme inactive and stop that particular pathway. Similar mechanisms are involved in the expression of genes and therefore the production of proteins within the cell. Some specific methylation reactions include the methylation of phenols which detoxify them and thereby aid in their excretion. (Stramentinoli 1987) In the context of this dissertation, methylation is also central to the metabolic chemistry of serotonin (and therefore also melatonin). The activity of both these compounds is effectively regulated by the presence of a methyl group. SAMe is synthesised from methionine, a naturally occurring amino acid. As the name implies (METH-ionine), it contains a methyl group. By utilising the energy supplied by ATP and in the presence of magnesium, it is converted into SAMe. The process is catalysed by the intervention of the enzyme MAT (methionine adenosyl Analysis of SAMe as an Antidepressant Analysis of SAMe as an Antidepressant S-Adenosyl-Methionine (SAMe) And Improved Methylation Offer A Serious Alternative To Orthodox Medications Can S-Adenosyl-Methionine (SAMe) and improved methylation offer a serious alternative to orthodox medications in the treatment of depression? Abstract In this dissertation we consider the issues surrounding the use of SAMe as an antidepressant. There are many different aspects to this consideration. We start by a consideration of exactly what depression is on a clinical basis and examine the psychological and physiological changes that characterise the condition. We then consider and examine the evolution of the current forms of antidepressant medication. We explore the fields of neurochemistry and pathophysiology of depressive states with particular emphasis on the chemistry of the methylation reaction and its relevance to the SAMe compound. Consideration is then given to SAMe specifically as a medication and the evidence that there is to support its apparent beneficial effect in depression. This is then expanded with a review of the chemistry of SAMe and its interactions with other biologically active entities. We conclude the exploration with a critical review of the published literature that is relevant to the role of SAMe as an antidepressant agent. Introduction In order to investigate the full extent of the question at the heart of this dissertation we must examine a number of background issues in some detail first. Depression is a complex clinical state. It has been said that there are as many theories about the aetiology and treatments for depression as there are clinicians thinking about the problem. (LeDoux, J. 1996). A brief examination of the literature on the subject tells us that this comment, although clearly intended to be flippant, may not actually be so very far from the truth. Perhaps it is because of the plethora of hypotheses, ideas and theories on the issue that there are also a considerable number of forms of treatment that are commonly employed. It has to be admitted that some are rational and some appear to be completely irrational. In this dissertation we shall examine some of the more rational forms of psychopharmacology in order to understand the place of SAMe in the therapeutic pharmacopoeia. Depression is a commonly occurring illness. It will significantly affect between 10-25% of women and approximately half that number of men during their lifetimes. Approximately 5 million people in the UK will experience significant depression in any given year. (Breggin 1994) If you suffer from an acute or chronic illness you are even more likely to suffer from depressive states with frequencies ranging from 30-50% depending upon the nature and severity of the illness. (Robertson et al 1997) What is depression ? There are many definitions of clinical depression and indeed many different rating scales which purport to try to quantify it. It is important to distinguish between clinical depression and simply feeling down or miserable. Depressive illness typically occurs in episodes although in some cases it can actually last for many months or even years. (Skolnick, P. 1999). One severe depressive episode is a major independent risk factor for getting further episodes. In other words, having had depression once you are statistically considerably more likely to have another attack. (Post RM. 1992). For our purposes we shall consider a practical overview of the nine classic symptoms that characterise classical depression 1. Depressed mood for most of the day 2. Disturbed appetite or change in weight 3. Disturbed sleep 4. Psychomotor retardation or agitation 5. Loss of interest in previously pleasurable activities; inability to enjoy usual hobbies or activities 6. Fatigue or loss of energy 7. Feelings of worthlessness; excessive and/or inappropriate guilt 8. Difficulty in concentrating or thinking clearly 9. Morbid or suicidal thoughts or actions. (After Zuess 2003) The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) states that in order to merit a diagnosis of clinical depression you need to demonstrate at least five of these symptoms and that they represent a change in your life. Mood alterations are commonplace in depressive states. The depressed patient will classically feel despair or sadness. Pleasure becomes an alien emotion as they tend to progressively loose interest in activities that they would have previously enjoyed. Mood swings can also occur although they are more commonly found in bipolar states (manic depression). Subjective feelings of tension or irritability are often described as well as just sadness. (Duman et al 1997) In addition to mood changes, depression can also produce changes in the emotional state as well. Feelings of worthlessness and guilt are perhaps the commonest emotions in the clinical spectrum. This is closely followed by both ineptitude and lack of confidence in ones own abilities or capabilities. It is common for depressed people to take action that avoids them having to take responsibility because of an overwhelming fear of failure. (Altar CA 1999) Somatic manifestations of depression are perhaps easier to quantify as they have a qualitative characteristic about them as opposed to the purely subjective. Changes in appetite are commonly found. Generally it is an anorexic change with a decrease in appetite and a loss of interest in food generally. Less frequently, the converse is observed with a voracious increase in appetite (comfort eating) which is normally associated with weight gain. This weight gain can be quite substantial in extreme cases. Sleep disturbances are commonplace. Insomnia and early waking are perhaps the commonest of this type of symptom. This can occur despite severe subjective symptoms of somatic tiredness and fatigue. Some people will find that fatigue is a prominent symptom and may find that this is translated into excessive sleeping and motor retardation generally. Fatigue is actually more difficult to quantify, but it is commonly experienced by the depressed patient. It can either be an overwhelming tiredness (lack of energy) or perhaps lack of stamina (tiring too easily). Associated with this is often a reduction in libido and, if severe, impotence can also occur. It is not unusual to find sexual avoidance behaviours developing in these circumstances. (Janicak et al 1989) Concentration is commonly impaired. Generally speaking the greater the degree of depression, the greater is the degree of concentration impairment. Thinking and reasoning processes slow down and the attention span is often markedly reduced. Students find they can have an inability to study and if severe, patients report an inability to even sit and watch television. (Bazin et al 1994) Somatic symptoms can occur without the psychological elements of the depression being apparent or obvious. This is a common clinical dilemma. Patients may enter a phase of denial or minimisation where they will not accept that they are actually depressed. They can try to rationalise their physical symptomatology into other disease processes. This can be mistaken for hypochondriasis. (De Vanna et al 1992) If depression is severe (or occasionally part of a symptom complex of another underlying pathology), then psychosis can be found. Delusional states are not uncommon in severe depression. Hallucinations can occur, but they are comparatively unusual. Patients can state that they hear voices telling them that they are worthless or perhaps instructing them to kill themselves. Although this is consistent with a depressive diagnosis, one should note that other illnesses such as schizophrenia must clearly be considered and excluded before a confident diagnosis of depression can be made. The actual basis or specific triggering factors for depression are not yet clearly defined but we do know that a number of different biological factors are relevant. Environmental factors, together with both genetic and neurobiological elements are all capable of influencing the overall clinical picture. (Kendler KS, 1998). Depression is broadly divided into endogenous and reactive types. In general terms endogenous depression is thought to be influenced the genetic and neurobiological factors whereas reactive depression may well have environmental factors as being relevant. This has considerable implications in our considerations of the possible actions of SAMe. (Gold et al 1988) Pharmacology of depression This is a vast subject and is generally considered to be a sub-speciality in its own right. It has long been recognised that certain substances appear to be able to exert a mood elevating effect. The advent of modern psychopharmacology allowed us to develop an understanding into just how some of these substances work. The drugs and medicines that are in common use today are the result of a process of evolution that, arguably, began with the uses of herbs at the beginning of recorded history and progressed to the chemically and biologically sophisticated compounds that are in use today. (Peinell and Smith 2003) In order to put the SAMe compounds into their appropriate place in the continuum we need to look at some of the evolutionary developments in the field. Most of the currently used antidepressants work by interfering in some way with the actions of the various neurotransmitters in the brain. Many work by slowing down the biological processes of degradation or destruction of these neurotransmitters. In purely simplistic terms, this results in a greater concentration of the neurotransmitter at the critical synaptic interfaces within the brain. (Levine et al 1998) The first real breakthrough with what could be considered to be a major therapeutic agent for depressive states came with the discovery of the MAOI (Monoamine Oxidse Inhibitors), group of drugs. Three were commonly used in clinical practice isocarboxazid, phemelzine and tranlcypromine. For a while they were used extensively but it became obvious that they had serious drawbacks including some potentially fatal side effects. (Saarelainen et al 2003), Headaches dizziness and tremor were not unusual accompaniments of the drug. They also had the ability to interact with other medications and certain types of food (tyrosine containing foods such as cheese could cause hypertensive crises). Despite these drawbacks, many patients were willing to take them because they indisputably worked. (Skolnick 1999) In time, the MAOis were superseded by the Tricyclic group of drugs. There were four in common use, namely amitriptyline, desipramine, imipramine and nortriptyline. These were generally speaking, marginally more effective than the MAOIs but they were without the worst of the side effects. Despite that, they were still able to cause dry mouth and blurred vision in some people. Constipation and drowsiness were not unusual and they were not commonly used if a person also had hypertension. The pharmaceutical industry then produced a number of different categories of medication in fairly quick succession. SSRIs (Selective Serotonin Reuptake Inhibitors), SNRIs (Serotonin and norepinephrine reuptake inhibitors) and NDRIs (Norepinephrine and dopamine reuptake inhibitors) all emerged into the market place. (Smith et al 2004) It is probably fair to say that they all had their niches in the therapeutic spectrum but the SSRIs were seen to corner the biggest share of the clinical market with citalopram, escitalopram, fluoxetine, paroxetine and sertraline as examples of the group. Fluoxetine was probably the most widely used and its trade name, Prozac was accepted almost as a household word. The side effect profile of this particular group was certainly less significant than their predecessors, but nausea and headaches were not uncommon. (Stewart et al 2000), The SNRIs fell into disuse largely because of their reputation in raising cholesterol levels and the NDRIs were found to cause unacceptable agitation in certain groups. There was then an emergence of a group of drugs which not only blocked the mechanisms that removed the trophic neurotransmitters from the synapse they also had an effect which effectively enhanced their action by blocking the action of the inhibitory neurotransmitters at the same time. There are several types of medication in this category, but perhaps the best known is maprotilene. Like most of the other types of effective medication, it is not without side effects. Drowsiness, nausea, dizziness and a dry mouth are common accompanying symptoms of a therapeutic dose of this medication. (Harmer et al 2003) Neurochemistry and pathophysiology of depression So far we have take a brief and admittedly comparatively simplistic tour of the nature and pharmacology of depression. We shall now look at the neurochemistry and pathophysiology of certain relevant aspects of the subject in more detail. In general terms, stress and antidepressants appear to have reciprocal actions on neuronal growth and to some extent, on their activity (see on). This appears to be through the mediation of various neurotrophins and the action of synaptic plasticity mainly in the region of the hippocampus and some other brain structures (Reid et al 2001). Various stresses appear to disturb and disrupt the activity, both of individual neurones and also larger functional groups, or networks of neurones whereas antidepressants appear to antagonise this disruptive ability. (Henke 1990) There is a large body of opinion which agrees with the hypothesis that regulation of synaptic activity is a major key to the pathophysiology of depression and related disorders. (Drevets et al 1997) The discovery of the MAOI group of drugs (above) led researchers to speculate that the monoamine group of neurotransmitters were central to the aetiology of depression. As more research is done it is becoming apparent that this may not actually be the case. It is now considered more likely that the fundamental problems lie further along the metabolic cascade from the monoamine oxidase activity. It is also considered likely that the pathology may well not be just a chemical imbalance, but may well involve other functions of neural tissue such as various cellular changes in physiology, genetic factors and the ability of neuronal network to change their characteristics. (Czyrak et al 1992) Observational studies have suggested that early life experiences, the impact of stress and the presence or absence of social support or interactions all have an influence on the development of a depressive state. (Gould et al 1998).Consideration of the monoamine chemistry clearly does not account for all of these factors although it is clearly acknowledged that it does play an important contributory role. Some recent work relating to the chronic use of different classes of antidepressants (Duman et al 1997), has appeared to show that they all are able to increase the production of the neuroprotective groups of proteins which, amongst other actions, play a central role in the plasticity of neurones. Current thinking is that this may well be a common function of a number of different pathways that the different antidepressants exploit. It is known that increases in monoamine levels in the synaptic region result (by a number of different mechanisms) and are associated with the induction of enzyme systems that control gene expression within the neurone. This can be inferred from the finding of increases in the levels of messenger RNA which codes for the cAMP response element binding protein (CREB). These levels slowly increase with chronicity of administration of antidepressants and this mechanism may well account therefore for the commonly observed slow and progressive onset of action of most of the antidepressant drugs. It is proposed that CREB triggers the production of BDNF (Brain Derived Neurotrophic Factor). This is significant since other work has shown that stress antagonises the levels of BDNF which is opposed by the actions of the antidepressant drugs. (Smith et al 1995). Further credence is given to this theory with the discovery that placing BDNF directly into the brain of experimental animals appeared to relieve many of the behaviour patterns that are associated with depression (Siuciak et al 1997) Some authors have suggested that depression may represent a particularly subtle form of neural degenerative disorder as it has been shown that the hippocampus becomes progressively atrophic in chronic depressive states. This is particularly significant as BDNF is thought to reverse such findings. (Shah et al 1998). There is associated supporting evidence in the form of a study by Vaidya (et al 1999) which shows that ECT treatment (which was always assumed to be detrimental to the neural structure and physiology) is associated with both increased levels of BDNF and trophic changes in the hippocampal neurones. A paper by Czyrak (et al 1992) looked at the antidepressant activity of SAMe in mice and rats in a way that clearly is not possible in humans. It is not always possible to directly extrapolate findings from animals to humans, but there are some pieces of evidence in this work which strongly implicate SAMe in the pathogenesis of depression. The paper itself is extremely long and complex but the relevant parts to our considerations here are the fact that normal geographical exploratory behaviour in rodents tends to diminish if a depressive state is induced. To some extent, exploratory behaviour is therefore considered a marker for the depressive state. It was found that SAMe tended to increase exploratory activity in mice. This, and other more sophisticated testing of the pharmacological interactions of SAMe showed that it tended to have the same psychopharmacological profile as many of the mainstream antidepressants. Many of the neurotransmitters and for that matter some neuroactive hormones have been variously implicated in the aetiology of depression (eg thyroid hormones and noradrenaline). (Nemeroff, 1998). Modern research has most consistently found that alterations in the levels of serotonin (5-HT) (Melzter H, 1989), system and the chemicals of the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis. (Kathol et al 1989), as the most consistently implicated mechanisms that appear to be associated with the control of the mood stabilising and regulating mechanisms. It is in fact very likely that both these mechanisms are in some way interlinked as part of the regulatory mechanism of mood. We have already referred to the role of stress in the aetiology of depression. We know that the adrenal glucocorticoid hormones subtly interact with the 5-HT system and these are produced in direct response to stress. (Lopez et al 1999) (I). We also know that the glucocorticoids have a number of direct effects on the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis. It may be that this is the mechanism by which stress antagonises the changes brought about by SAMe. (Lopez et al 1999) (II) We do not need to consider the effects of the corticoids on the LHPA axis in detail as it is only of peripheral relevance to our considerations here. The important consideration in this regard is that the LHPA axis is intimately connected to the hippocampus. It is this structure that is the intermediate step and connection between the bodys hormonal response to stress and the response of the higher functions of the brain. (Dallman et al 1987). The immediate relevance of all this to the actions of SAMe are that hyperactivity of both the hippocampus and the LHPA axis are both well documented in cases of clinical depression. This has been shown to also be associated with high levels of corticosteroid production (Kalin et al 1987), but one study has shown that in suicide cases who have had profound depression the hippocampus has fewer corticosteroid receptor sites than one might normally expect (Lopez et al 1998). One further piece of clinical evidence in the role of the corticosteroids in depression is that patients with Cushings disease have a high incidence of depression. This incidence returns to normal when their hormonal over-activity is treated and returned back to physiological levels. (Murphy 1991) SAMe as a medication SAMe was discovered in Italy in 1952 during research into the chemistry of neurotransmitters. It was not, however, introduced in a useable form for patient benefit until 1974 (as SAMe sulphate-paratoluene-sulphonate). It is for this reason that the majority of the early papers and work on the subject are almost exclusively Italian in origin. (De Vanna et al 1992) SAMe has been used clinically in a number of conditions including cholestasis, osteoarthritis and depression. (Carney et al 1987) Although there is a wealth of literature on the first two elements it is not relevant to our considerations here. We shall therefore restrict this discussion to the spectrum of its use in the field of depression. A number of studies have shown that SAMe has useful activity in depressive illness. Studies that have compared it to placebo have found that it can consistently produce about a 6 point increase on the Hamilton rating scale after about three weeks of optimum treatment. This finding is approximately in line with the results that are found with most of the other clinically effective antidepressant medications. (Cooper et al 1999) (De Vanna et al 1992) Some studies have found that using SAMe in a large dose has produced an unusually rapid onset of beneficial effects (Kagan 1990) One could argue that, because it is a naturally occurring substance, it would not be likely to have a high side-effect profile. Although these two statements do not always follow, it is generally true. A study by Bressa (1994) on the issue showed that it did have a particularly low side-effect profile, particularly when compared to the other antidepressants (Tricyclics). To demonstrate this point further, we can point to the study by Caruso (et al 1987) where there were a greater number of patient withdrawals due to the side effects of the placebo than withdrew because of the SAMe drug. For the record, that particular trial was in its use as an antiarthritic rather than an antidepressant, but the point is made. The two major unwanted clinical effects are nausea and hypomania. The nausea is not a local effect on the gut lining but appears to be a centrally mediated effect and is possibly caused by the same phenomenon of over-stimulation of the neuronal networks which causes the other major clinical manifestation of hypomania. For this reason it is generally not used in cases of bipolar disorder. (De Vanna et al 1992) It is probably not strictly accurate to refer to SAMe as a drug as it is normally found in the cellular matrix. It has been found to be effective in patients who have been unable to tolerate other forms of antidepressants or, for that matter, have had minimal response to them. (Reynolds et al, 1984) Young (1993) produced a particularly interesting review of dietary treatments for depression. A lot of his article is not relevant to our considerations here, but he makes a number of interesting and relevant observations. Low serotonin levels are known to be associated with depression even though low levels on their own do not appear to cause the condition. It appears that it needs to be in combination with a low level of folic acid. We know that low levels of folic acid are also often found in combination with depressive illness and that low levels of folate are often associated with low levels of SAMe. The evidence points to the fact that the low levels of serotonin are more likely to be a result of the low SAMe levels in neural tissue and that this is more likely to be nearer to the root of the main anomaly that causes depression. Pregnancy is known to be associated with low levels of folate and post natal depression is a well recognised clinical entity. Salmaggi (et al 1993) considered the effects of SAMe in the postnatal period. This was a well considered and constructed study. It was a double blind placebo controlled trial over a 30 day period and had an entry cohort of 80 women. The degree of depression was assessed before, during and after the trial on the Hamilton Scale. The results showed a statistically significant improvement in the SAMe group when compared to the placebo group. The authors comment that there were no significant side effects of the medication encountered. Because we know that any beneficial effect that SAMe is likely to have on a patient tends to be seen more quickly than with the other antidepressants, and also, by virtue of what we suspect about its probable mode of action in the hippocampus and elsewhere in the brain, it seems a logical step for someone to look into the effects of giving SAMe alongside a conventional antidepressants to see if there is either any synergistic effect or possibly a speeding up of the clinical onset of the secondary medication. The study by Berlanga (et al 1992) did exactly that. Unfortunately the trial was not particularly rigorous in its design as although it was double blind, it was not placebo controlled, which would appear to have been the method of choice in this type of investigation. Its other problem as that it only had an entry cohort of 40 patients. Despite these limitations it was indeed shown that depressed patients who took SAMe in conjunction with other antidepressant medication found that the depressive symptoms resolved faster with the SAMe added to their normal treatment regime. There are one or two other less important papers which we shall only mention in passing. Kagan (et al 1990) ran a small trial on 15 inpatients (with very severe depression) and found SAMe to be a safe, effective antidepressant with few side effects and a rapid onset of action. This particular trial is notable as it was the first to report the side effect of mania in a patient who didnt have a previous history. Another is the trial by Rosenbaum (et al 1990). This particular trial is notable for the demonstration of the fact that about 20% of other treatment resistant patients experienced benefit with SAMe. Faya (et al 1990) (II) considered the fact that SAMe is thought to exert its effect through its action in increasing dopamine levels in the synaptic cleft. It is known that dopamine inhibits the production of both Thyroid stimulating hormone (TSH) and Prolactin from the pituitary gland. Faya considered measuring the levels of both TSH and Prolactin during treatment with SAMe. His findings constituted something of a surprise insofar as in the men in the trial group had their levels of TSH and Prolactin reduced which is consistent with the hypothesis that SAMe increases the dopamine levels in the brain. Much to everybodys surprise, this effect was not seen in the female group. The authors do not offer any explanation of this fact. For the record, there is another trial (Thomas et al 1987), which obviously considered the same phenomenon and their trial did not show any sex linked difference in the suppression of the Prolactin levels With regards to efficacy, a trial by Carney (et al 1986) suggests that the beneficial action of SAMe is restricted to endogenous depression and it does not appear to have any action above placebo on reactive depression. As far as we can ascertain, this is the only trial published that has made this suggestion, although from a first principles basis, one can see the biochemical rationale for believing that it might well be the case. On a purely empirical grounds, some authors have recommended (on the basis of scant hard evidence), that SAMes action can be maximised by the addition of B12, B6 and folic acid. It is known that SAMe is required to convert these agents into their active form as a coenzyme. (Morrison et al, 1996). The same author also recommends the simultaneous adminstration of Trimethylglycine (TMG) which is necessary for the intracellular conversion of methionine into SAMe by the provision of the necessary methyl- groups. Comment has to be made that again, this appears to be a completely empirical (and logical) suggestion, but we cannot find any hard evidence to substantiate its clinical use. Chemistry SAMe is a basic component of cellular biochemistry. It occurs in every living cell and is second in importance only to ATP in both the number variety and significance of the reactions in which it serves as a cofactor. (Stramentinoli 1987). It is central in the chemistry of the transmethylation reactions. In essence its cellular function is to transfer the active methyl group form carrier molecules to a multitude of other molecules. In general terms, this methylation makes inert molecules biologically active. In addition to the transmethylation reactions it also plays a central role in transsulfuration and aminopropylation reactions It is involved in the synthesis of proteins including the nucleic acids, fatty acids, lipids and phospholipids, porphyrins and polysaccharides. In terms of our considerations here, perhaps the most significant reaction type that SAMe is involved in is the generation of the neurotransmitter amines. In this regard it is considered to be the most biologically significant provider of methyl groups within the cell. (Baldessarini 1987). Significantly it is also involved in the pathways to produce a number of other neurologically active compounds such as adrenaline, the neuronutrients acetyl l-carnitine and phosphatidyl choline (Mathews et al 1990) It is also to be found in the metabolic pathways of both serotonin and dopamine. Oral administration has been shown to increase the metabolites of these compounds in the CSF (implying increased turnover). It is thought to exert its antidepressive effect partly through the mechanism of increasing the levels of both dopamine and serotonin as neurotransmitters, but it also appears to have some form of trophic action on some of the neurones in the brain cortex. (Baldessarini 1987) It has been demonstrated that the tissue levels of SAMe tend to diminish with age and blood levels are also found to be low in some cases of clinical depression (Baldessarini 1987) A methyl group (CH3) is a group of three hydrogen atoms bound to one carbon atom. It does not exist in a stable isolated form and is transported between molecules by intermediaries such as SAMe. Methylation is the process by which this group is transferred from the methyl donor molecule to the recipient molecule. In general terms this process is central to the control of many of the intracellular pathways. Giving a methyl group to an enzyme is often the key to activating it, and thereby beginning a synthesis or degradation process elsewhere in the cell. Equally removing the methyl group will render the enzyme inactive and stop that particular pathway. Similar mechanisms are involved in the expression of genes and therefore the production of proteins within the cell. Some specific methylation reactions include the methylation of phenols which detoxify them and thereby aid in their excretion. (Stramentinoli 1987) In the context of this dissertation, methylation is also central to the metabolic chemistry of serotonin (and therefore also melatonin). The activity of both these compounds is effectively regulated by the presence of a methyl group. SAMe is synthesised from methionine, a naturally occurring amino acid. As the name implies (METH-ionine), it contains a methyl group. By utilising the energy supplied by ATP and in the presence of magnesium, it is converted into SAMe. The process is catalysed by the intervention of the enzyme MAT (methionine adenosyl