Documentary Film assignment (Roger and Me) Movie Review

Documentary Film assignment (Roger and Me) - Movie Review Example The film counteracts the modern management and moral pragmatism all in opposition to the mentality in the search for excellence. In the real sense, this movie comprises of corporate newspeak message. Analysis of the importance of profits in the large corporations at the peril of the workers life in provided. In this interesting documentary, there is a procedural indicator of daily flaws in the society. Moore deploys dialects in the film medium to label the face of true capitalism in real life. The most outstanding scene is where Smith gives a speech in Christmas television while, on the other hand; Moore demonstrates the eviction of GM worker. There is a direct correlation between the manipulative nature of corporates and Christmas ceremony hence justifying some heartless nature. Moore is more of a critic unto the stakeholders in the American corporate world. As per the film there is much negativity with some minimal truth hence Moore proves to be unfair. He is also an individual who portrays that corporate neglects and poverty counts as sins hence appeals to minimal

Twilight is not literary genius Essay Example for Free

Twilight is not literary genius Essay What defines a â€Å"bad book†? Most people can identify what they liked about a book: the characters were believable or the writing was beautiful or the plot was striking, etc†¦; however, when asking someone what they did not like about a â€Å"bad book†, they can scarcely put their finger on it. Presented in this essay is a definition for a â€Å"good book† upon which three books (The DaVinci Code by Dan Brown, I Am Legend by Richard Matheson and Twilight by Stephenie Meyer) will be examined and determined as â€Å"good† or â€Å"bad†. A good book can be defined with the use of three basic concepts: plot, prose and character development. The plot is essential. If the plot of a novel is lacking, almost assuredly all other points will follow. Prose, the wording and grammar of the novel, is the first contact the reader has with your novel. If the prose is bad, the likelihood that someone will want to read the book (or be able to read the book) decreases. Character development may be the single most important aspect of a novel. The characters and their decisions are what ultimately drive a story. If a character is dull, unlikeable and or even not relatable, the book will most assuredly be bad. These are not the only methods to judge a book, but they are usually the aspects a reader will be looking at first and foremost. The DaVinci Code by Dan Brown is one of the highest selling books in the 21st Century. It has been translated into numerous languages and has had a film adaptation; however, it is also ridiculed by many as being a bad book. The book, being a mystery, is packed full of action. There are clues to be solved, puzzles to solve and a whole society full of mysteries to crack. The plot is interesting and Brown puts in a number of twists that keep the reader guessing and reading; although, there have been a number of critics on Brown’s bestseller being historically and scientifically inaccurate. The prose used in The DaVinci Code is so lacking that it is almost comical. Brown, despite being a bestselling author, does not seem to grasp grammar or fluidity sentence structure. The first page in the novel demonstrates this: A voice spoke, chillingly close. â€Å"Do not move. † On his hands and knees, the curator froze, turning his head slowly. Only fifteen feet away, outside the sealed gate, the mountainous silhouette of his attacker stared through the iron bars. He was broad and tall, with ghost-pale skin and thinning white hair. His irises were pink with dark red pupils (Brown, 2). â€Å"Chillingly close† denotes that the speaker is close directly behind or whispering into ones ear. Only a few sentences down, Brown reveals that his version of â€Å"chillingly close† is fifteen feet away. Also, when one is frozen they do not turn their head. If the curator was truly frozen, his head would not be turning. Also, it is impossible to see the skin, hair and eye color of a silhouette – a silhouette is a black figure with no apparent qualities, it is a black shadow. The character development in The DaVinci Code is also lacking. The main characters, Robert Langdon and Sophie Neveau are likeable enough. We learn some of their background and history, but other than that they remain mysteries. The villains in this story are all one-dimensional. They are all connected to the Catholic Church or some sort of secret society and none have anything other than tainted motives at best. Most of the other characters were written stereotypically: the British lord turned evil, the evil Albino, etc†¦ The DaVinci Code, although a suspenseful page-turner, was a poorly written book. The plot was full of twists and turns that kept the readers’ attention, but was full of inaccuracies. The prose was dreadful at best. The character development was nearly non-existent, relying on stereotyping rather than explanation. I Am Legend by Richard Matheson is a post-apocalyptic novel in which the entire human race, with the exception of one man (Robert Neville), has turned into a vampire. He spends his days staking vampires and his nights barricaded in his house waiting for the sun to rise. This book has inspired more than one movie adaptation. The action scenes are remarkable in the way they are described. The simple clarity of what is going on while the vampires are banging on the walls and defenses of Neville’s house at the beginning of the book sets the tone for the rest: â€Å"He sat in the living room, trying to read. He’d made himself a whiskey and soda at his small bar and he held the cold glass as he read a physiology text. From the speaker from over the hallway door, the music from Schoenberg was playing loudly† (Matheson, 12). The plot of this book seems simple at first: Neville is the last man on Earth who is not infected and he kills the beings that are. This book is character-driven rather than plot-driven. The prose of this novel has a flowing simplicity to it. Matheson does not need to use flowery wording or beautiful metaphors. â€Å"The sky was darkening and it was getting chilly. He looked up and down Cimmaron Street, the cool breeze ruffling his blonde hair. That’s what was wrong with these cloudy days; you never knew when they were coming† (Matheson, 12). His manner of writing brings a depth to the story and helps sets the tone of the post-apocalyptic world. He doesn’t need to compare the sky to anything or the breeze. He writes the way the main character’s world would seem: simple and dark. Neville eats, sleeps, hides and kills vampires. The character development for I Am Legend is remarkable. In the beginning, the reader sympathizes with Neville. What would it be like to be in a world by yourself? Fighting to survive every moment? As the book continues, the reader watches as Neville slowly becomes different, turning into a monster himself. I Am Legend is a good book. The action is detailed, the prose is simplistic but useful, the plot is character-driven and the character development for the main character is enthralling. I Am Legend is anything but a bad book. It seems as though vampires always make a comeback. They were present in I Am Legend, written in 1954, and they appear again in the recent phenomenon of the Twilight Saga by Stephenie Meyer. Twilight is the first of a four book saga about a family of â€Å"vegetarian† vampires (vampires who feed only on animals rather than humans) and the human girl that a member of the family falls in love with. The plot for Twilight is filled with cliches: the basic Romeo and Juliet love story, a forbidden love. The idea of a vampire who does not feed on human beings – Anne Rice, for instance, had a similar idea. A misfit high school teenage girl with a strange ability (brain-dead-ness? ) happens more times than not. Most people love a good love story, which is essentially what Twilight thrives for, the love between the hero (Edward Cullen) and the heroine (Bella Swan). The prose used in Twilight is not literary genius by any means. There are numerous repeated adjectives, descriptions of Edward that are also repetitive for example: â€Å"His skin, white despite the faint flush from yesterday’s hunting trip, literally sparkled, like thousands of tiny diamonds were embedded in the surface† (Meyer, 260). There are numerous times in the novel when Edward’s skin is described as diamond-like the way it shines. It is written simplistically, but as it is a teenage, love-struck girl who is narrating it, perhaps too flowery of words would seem out of character and strange. The character development in Twilight is limited. This could be because the story is written from a first-person perspective, limiting the reader to know only what Bella knows. Bella, as a character, is well-defined. She isn’t comfortable in her own skin, she is clumsy and smart. Edward, however, seems to have more mood swings than a teenager, despite his age of well over a century old. In fact, he sums his whole personality up in one sentence: â€Å"How easily frustrated I am† (Meyer, 265). The high school teenagers Bella is friends with are stereotypical at best; Charlie Swan is exactly what you would expect from a small-town sheriff, there is very little learned about the Cullen Family (although that does come later in the series) and the villains James, Laurent and Victoria are one-dimensional. They seem to be after one thing and one thing only: blood. Twilight has a predictable plot, limiting and repetitive prose and inadequate character development in her full cast of characters. By the definitions set out by this essay, Twilight by Stephenie Meyer is a poorly written, bad book. In conclusion, out of the three books examined in this essay: The DaVinci Code by Dan Brown, I Am Legend by Richard Matheson and Twilight by Stephenie Meyer, the only book that can truly be identified as a good book is Matheson’s I Am Legend; however, all three books have been phenomenon’s, selling millions world-wide in a multitude of languages and all have had silver screen adaptations. Despite what who says these books are good or bad, the general public are frantic about them regardless. Works Cited Brown, Dan. The DaVinci Code. New York: Random House, 2003. Matheson, Richard. I Am Legend. New York: Tom Doherty Associates, 1997. Meyer, Stephenie. Twilight. New York: Little, Brown and Company, 2005.

History of the West Nile Virus Essay -- Biology Medical Biomedical Dis

History of the West Nile Virus Abstract West Nile virus (WNV) is a virus that is transmitted by mosquitoes. It has been found in humans, birds, and other animals, typically in Africa, Eastern Europe, and the Middle East. In 1999, WNV was detected in the United States for the first time, and since then it has spread across the U.S. According to the U.S. Centers for Disease Control and Prevention (CDC), over 15,000 people in the U.S. have tested positive for the WNV infection since 1999, including over 500 deaths. Many more people have likely been infected with WNV, but have experienced mild or no symptoms. What is the history of the West Nile virus? West Nile virus is an emerging infectious disease that can cause encephalitis (inflammation of brain tissue) and or meningitis (swelling of the tissue that encloses the brain and spinal cord). West Nile virus is a newly emergent virus of the family Flaviviridae, found in both tropical and temperate regions. Its group is classified in Group IV (gram(+) single stranded, RNA). Its genus is Flavivirus. It?s commonly found in Africa, West Asia, the Middle East, and more recently; North America. It may result to serious illnesses if not reported to the hospital in time. Knowing its history, how it?s transmitted, symptoms, treatment, and prevention will probably keep one from getting it. In 1937, West Nile virus was first discovered in a feverish woman in the West Nile district of Uganda in Central Africa. The virus became recognized as a cause of severe human Meningoencephalitis (inflammation of the spinal cord and brain) in elderly patients during an outbreak in Israel in 1957. In the early 1960?s, Eastern Equine Encephalitis (affecting horses) was first found in Egypt and France (We... ... people may need to go to the hospital where they can receive supportive treatment including intravenous fluids, help with breathing, and nursing care. To help prevent WNV: Empty plastic wading pools at least once a week or store in a position that water will drain. Make sure your backyard pool is maintained properly. It is though that once a person has recovered from WNV, they are immune for life to future infections with WNV. This immunity may decrease over time or with health conditions that compromise the immune system. As long as people get older or immune system is weak you may end up getting it again. This is very important because just to know if people can get it again when there immunity isn?t work very good. The U.S. government and its citizens should care WNV 4 because there is no vaccine to cure it or it can mutate and get even harder to fight it off.

Why My Education Is Important

Why My Education is Important? I often dream about having a successful career in the business world, but to achieve this goal, I must have an education. Education is extremely important to me. In the business world, success depends on lots of knowledge. In my opinion, education is the foundation of life, and it also increases my knowledge around the world. However, the most important thing about education is that education opens up the window of opportunities. The world of business is a very complicated place in which to survive.For example; the stock market can change it's mood every single day. What I mean by that is, a stock can change its value at any moment. People who are involved in the stock market struggle between becoming poor or becoming rich. To be able always to stay on the winners side, I need lots of education. Education helps me to make good decisions in the business world and for my life. Not just in business, education will also benefit me throughout my life, person ally and socially. An education should help me to have less financial problems. It will enable me to become independent.My educational experiences have provided me with many opportunities to solve problems in every day life. The education which I have received in history classes,for instance, has provided me with cultural information from every country. I believe education will help to build a circle of people who will be important to me in my career in the future. In summary, why education is important to me? Education helps me to understand the business world. It prepares me for a better future and numerous other things of which at this time I am unaware.The most important reason education is so important to me is that education opens windows for me and it gives me opportunities for a better quality of life. My parents and many of my teachers (Mrs. Kirker, Coach Bowman and many more) care about my education. They explain why education is important to me almost every time they have a chance. As a responsible teenage adult, I need to focus on my education and elevate my educational level, so that my chances of having a difficult future will be less!

Just Another Paper

Course Syllabus College of Criminal Justice and Security CJA/394 Contemporary Issues and Futures in Criminal Justice Copyright  © 2010 by University of Phoenix. All rights reserved. Course Description This course examines both the principle issues in contemporary criminal justice as well as the extrapolation of such issues toward possible futures within the criminal justice field. Students will focus upon relevant research in policing, courts, and corrections that reflect key elements of current conditions and what may be expected in the years to come.Students will apply critical review and engage in in-depth discussion of these concepts as a basis for comprehensive understanding at local, state, national, and global levels of criminal justice administration. Policies Faculty and students/learners will be held responsible for understanding and adhering to all policies contained within the following two documents: †¢University policies: You must be logged into the student websi te to view this document. †¢Instructor policies: This document is posted in the Course Materials forum.University policies are subject to change. Be sure to read the policies at the beginning of each class. Policies may be slightly different depending on the modality in which you attend class. If you have recently changed modalities, read the policies governing your current class modality. Course Materials Muraskin, R. , & Roberts. A. R. (2009). Visions for change: Crime and justice in the twenty-first century (5th ed. ). Upper Saddle River, NJ: Pearson/Prentice Hall. Robinson, M. B. (2009). Justice blind?Ideals and realities of American criminal justice (3rd ed. ). Upper Saddle River, NJ: Pearson/Prentice Hall. Victor, J. L. & Naughton, J. (2010). Annual editions: Criminal justice. New York, NY: McGraw-Hill. Walker, S. , & Katz, C. M. (2008). The police in America: An introduction (6th ed. ). New York, NY: McGraw- Hill. Waller, B. N. (2009). You decide! Current debates in crim inal justice. Upper Saddle River, NJ: Pearson/Prentice Hall. All electronic materials are available on the student website. Week One: Criminal Justice System AssessmentDetailsDuePoints Objectives1. 1Evaluate past, present, and future trends in the interface between components of the criminal justice system and criminal justice connections with surrounding society. 1. 2Assess the value of the criminal justice system in a changing society. 1. 3Examine contemporary issues currently facing the Criminal Justice System. 1. 4Identify recent and future trends and issues affecting the criminal justice system. ReadingsRead Ch. 1 of Visions for Change. Read Article 14 of Annual Editions: Criminal Justice. Read Ch. 3 of Justice Blind? Read this week’s Electronic Reserve Readings. ParticipationParticipate in class discussion by posting a minimum of two substantive responses on four separate days during the online week. All Week1 Discussion QuestionsRespond to the two weekly discussion que stions (DQ1 & DQ2). DQ1-Thursday DQ2-Saturday0. 5 0. 5 Individual AutobiographyIntroduce yourself to the class with a summary of your background. Submit the bio to the Chat Room forum and comment on other student’s bios in an effort to get to know everyone better.Tuesday by 11:59 PM MST4. 0 Individual Criminal Justice Trends EvaluationWrite a 1,400-1,750-word paper in which you evaluate past, present, and future trends in the interface between components of the criminal justice system and criminal justice connections with surrounding society. In your assessment, be sure to evaluate and identify and assess the following: †¢Recent and future trends and contemporary issues affecting the criminal justice system †¢Value of the criminal justice system in a changing society Format your paper consistent with APA guidelines.Monday by 11:59 PM MST12 Week Two: Past, Present, and Future Trends in Policing: Development and Operations DetailsDuePoints Objectives2. 1Evaluate past, present, and future trends pertaining to the continuing development and operation of the field of policing. 2. 2Analyze the organizational management, administration, and operational aspects of policing. 2. 3Examine perspectives of the policing function from the local, state, and federal organizational levels. 2. 4Identify possible future changes in laws and the impact on the field of policing.ReadingsRead Ch. 2-4, & 15 of The Police in America. Read Article 14 of Annual Editions: Criminal Justice. Read Debate 1 & 2 of You Decide! Current Debates in Criminal Justice. Read this week’s Electronic Reserve Readings. ParticipationParticipate in class discussion by posting a minimum of two substantive responses on four separate days during the online week. All Week1 Individual Discussion Questions Respond to the two weekly discussion questions (DQ1 & DQ2). DQ1-Thursday DQ2-Saturday 0. 5 0. 5 IndividualPolicing Functions PaperWrite a 1,050-1,750-word paper in which you examine the various perspectives of the policing function from the local, state, and federal organizational levels. Be sure to identify and address possible future changes in laws and the overall impact these changes will have on the field of policing. Format your paper consistent with APA guidelines. Monday by 11:59 PM MST11 Learning Team Team Charter Collaborate with all team members and come to consensus regarding the contents of your learning team charter. Submit the final Team Charter to one team member’s Assignments section.Wednesday by 11:59 PM MST1 Learning Team Policing Development and Operation Trends PaperWrite a 1,050-1,400-word paper in which you analyze the organizational management, administration, and operational aspects of policing within policing organizations. In your analysis, be sure to evaluate past, present, and future trends pertaining to the continuing development and operation of the field of policing and how these evolutions impact various policing organization s (local, state, federal). Format your paper consistent with APA guidelines. Monday by 11:59 PM MST8Week Three: Past, Present, and Future Trends of the Courts: Development and Operations DetailsDuePoints Objectives3. 1Identify the current and future issues facing courts and court administrators today. 3. 2Articulate court purposes and responsibilities and the importance of strategic planning and vision as foundations of successful court management. 3. 3Discuss future management issues and trends regarding language interpretation services. 3. 4Appraise the impact of court consolidation and restructuring on future court processes and responsibilities. . 5Assess the past, present, and future impact that victim rights laws have on court proceedings. ReadingsRead Ch. 12 of Visions for Change: Crime and Justice in the Twenty-First Century. Read Ch. 7 of Justice Blind? Read Article 13 of Annual Editions: Criminal Justice. Read Debate 3, 8, & 17 of You Decide! Current Debates in Criminal Ju stice. Read this week’s Electronic Reserve Readings. ParticipationParticipate in class discussion by posting a minimum of two substantive responses on four separate days during the online week.All Week1 Individual Discussion Questions Respond to the two weekly discussion questions (DQ1 & DQ2). DQ1-Thursday DQ2-Saturday 0. 5 0. 5 Individual Court Issues AnalysisWrite a 1,050-1,400-word analysis in which you identify the current and future issues facing courts and court administrators today. In your analysis be sure to discuss the following areas: †¢Discuss future management issues and trends regarding language interpretation services. †¢Assess the past, present, and future impact that victim rights laws have on court proceedings.Format your paper consistent with APA guidelines. Monday by 11:59 PM MST10 Learning Team Court Management Executive SummaryWrite a 350-700-word executive summary in which you articulate court purposes and responsibilities and the importance o f strategic planning and vision as foundations of successful court management. Additionally, appraise the impact of court consolidation and restructuring on future court processes and responsibilities as part of court management efforts and responsibilities. Format your paper consistent with APA guidelines. Monday by 11:59 PM MST7Week Four: Past, Present, and Future Trends in Corrections: Institutional and Corrections Systems DetailsDuePoints Objectives4. 1Identify the current and future issues facing prisons and prison administrators today. 4. 2Evaluate past, present, and future trends pertaining to the development and operation of institutional and community based corrections. 4. 3Analyze the role/issue of various correctional models, approaches and systems as a developing trend. 4. 4Analyze Legislative and correctional philosophies associated with increasing correctional populations. 4. Hypothesize future correctional problems including potential solutions. ReadingsRead Ch. 16 of Visions for Change: Crime and Justice in the Twenty-First Century. Read Article 31 & 32 of Annual Editions: Criminal Justice. Read Debate 13 & 15 of You Decide! Current Debates in Criminal Justice. Read this week’s Electronic Reserve Readings. ParticipationParticipate in class discussion by posting a minimum of two substantive responses on four separate days during the online week. All Week1 Individual Discussion QuestionsRespond to the two weekly discussion questions (DQ1 & DQ2).DQ1-Thursday DQ2-Saturday 0. 5 0. 5 Individual Corrections Trend EvaluationWrite a 1,400-1,750-word paper in which you conduct research and evaluate past, present, and future trends pertaining to the development and operation of institutional and community based corrections. As part of your evaluation, identify and analyze current and future issues facing prisons and prison administrators today and the role/issue of alternate correction systems as a developing trend. Format your paper consistent wit h APA guidelines. Monday by 11:59 PM MST12 Learning TeamFutures of Corrections PaperWrite a 700-1,400-word paper in which you analyze future correctional philosophies associated with increasing correctional populations. In your analysis be sure to hypothesize future correctional problems that will need to be addressed by prison administrators. Format your paper consistent with APA guidelines. Monday by 11:59 PM MST7 Week Five: Major Global Crimes and Criminal Issues in Criminal Justice DetailsDuePoints Objectives5. 1Identify major global crimes and criminal issues that have a global impact on justice systems and processes. 5. Compare and contrast international criminal justice systems. 5. 3Analyze the impact of cyber crime on worldwide justice systems. ReadingsRead Ch. 5, 15, & 32 of Visions for Change: Crime and Justice in the Twenty-First Century. Read Debate 18 & 19 of You Decide! Current Debates in Criminal Justice. Read this week’s Electronic Reserve Readings. Participat ionParticipate in class discussion by posting a minimum of two substantive responses on four separate days during the online week. All Week1 Individual Discussion QuestionsRespond to the two weekly discussion questions (DQ1 & DQ2).DQ1-Thursday DQ2-Saturday 0. 5 0. 5 Individual Global Crimes AnalysisWrite a 1,050-1,400-word paper in which you identify the various major global crimes and criminal issues that have a global impact on national and international justice systems and processes. Be sure to compare and contrast the various international criminal justice systems and how these major global crimes and criminal issues addressed. Format your paper consistent with APA guidelines. Monday by 11:59 PM MST11 Learning Team Article AnalysisWrite a 700-1,400-word paper in which you research a recent article focusing on cyber-crime.In your analysis, be sure to analyze the impact that cyber crime has on worldwide justice systems and the processes which combat global crime. Format your paper consistent with APA guidelines. Monday by 11:59 PM MST7 Individual Discussion Questions Week One †¢What is the relationship between the criminal justice system and society? How do past, current, and future trends impact the development of community relations for criminal justice organizations? What recommendations would you make to improve the interface between society and the criminal justice system? Give an example of a contemporary issue currently facing the criminal justice system. How does this issue impact the criminal justice system? What would happen if this issue was magnified (or decreased)? What would the implications be for the various personnel in the criminal justice system? Explain. Week Two †¢What are the various developmental and operational trends impacting policing? How do past, current, and future trends impact the development and operations of policing organizations? What recommendations would you make to improve the overall development and operations of the policing field? What are the various organizational police functions (local, state, federal)? How do the various functional levels of policing differ from one another? What distinctions can be made about each? Is there a better solution to the way the current system(s) operate at each level? Explain. Week Three †¢Give an example of a current/future issue facing courts and court administrators today. How does this issue impact the overall operations of the court system within the criminal justice system? How can we solve this issue to improve the court system and improve overall court administration?Explain †¢What are the laws reflecting victim rights? How do the past, present, and future victim rights laws impact court proceedings? What would happen if victim rights laws did not exist? Explain. Week Four †¢What is the role of alternate corrections systems? How do alternate corrections systems impact the criminal justice system as a developing trend regarding m anagement, administration, etc.? Is there a better solution to alternative corrections systems? Explain. †¢What are potential future problems for correctional systems? Which events have led to the development of these issues (past and present)?How can we solve and accurately plan to correct these future issues? Explain. Week Five †¢Give an example of major global crimes. How do these crimes and other criminal issues impact global criminal justice systems? How can we improve the overall effectiveness of strategies employed to combat these global crimes and criminal issues? Explain. †¢Give an example of an international justice system. How do the various international justice systems cooperate and coordinate in combating global crime? What would happen if the communication among these international justice systems broke down, or was non-existent? Explain.

Free Essays on Rene Descartes Meditations

After Descartes’ first meditation his problem becomes this; how can he be sure that any of his beliefs hold any truth? How can he be sure that everything isn’t just an illusion that is deceiving him such as a dream or that there isn’t a deceiver intentionally deceiving him? He finds that in order to move forward in his quest for true existence of god or the material world he must find a starting place of truth or as he puts it like Archimedes moving the earth, some fixed point of certainty. He finds this fixed point with his Cogito, the discovery that he himself must exist. Having already convinced himself that there is absolutely nothing in the world, Descartes is left to ponder if he himself does not exist as well. He finds this thought to be false because if he can convince himself of something then he must certainly exist. Further questioning this theory he finds that even if some deceiver of supreme power that is deliberately and constantly deceiving him that he must also undoubtedly exist because he is still thinks that he is something even if false, thus still existing. This now brings in the phrase â€Å"I am, I exist† or the more popular interpretation â€Å"I think therefore I am† Furthering that Descartes is essentially asking himself would it be possible for himself to believe that he existed, and this be false? He finds that even if he believes this false logic that he must still exist, because anything that believes or doubts something must exist. So if he does believe that he exists, then his belief must hold truth, because it would be impossible for him to hold that belief falsely do to his logic of existence. So he ascertains that if he can both persuade himself of something, and likewise be deceived of something, then surely he must exist. He essentially claims that every time he thinks something in his mind, he has proof that he exists. It is not possible to think without also existing. With this ... Free Essays on Rene Descartes Meditations Free Essays on Rene Descartes Meditations After Descartes’ first meditation his problem becomes this; how can he be sure that any of his beliefs hold any truth? How can he be sure that everything isn’t just an illusion that is deceiving him such as a dream or that there isn’t a deceiver intentionally deceiving him? He finds that in order to move forward in his quest for true existence of god or the material world he must find a starting place of truth or as he puts it like Archimedes moving the earth, some fixed point of certainty. He finds this fixed point with his Cogito, the discovery that he himself must exist. Having already convinced himself that there is absolutely nothing in the world, Descartes is left to ponder if he himself does not exist as well. He finds this thought to be false because if he can convince himself of something then he must certainly exist. Further questioning this theory he finds that even if some deceiver of supreme power that is deliberately and constantly deceiving him that he must also undoubtedly exist because he is still thinks that he is something even if false, thus still existing. This now brings in the phrase â€Å"I am, I exist† or the more popular interpretation â€Å"I think therefore I am† Furthering that Descartes is essentially asking himself would it be possible for himself to believe that he existed, and this be false? He finds that even if he believes this false logic that he must still exist, because anything that believes or doubts something must exist. So if he does believe that he exists, then his belief must hold truth, because it would be impossible for him to hold that belief falsely do to his logic of existence. So he ascertains that if he can both persuade himself of something, and likewise be deceived of something, then surely he must exist. He essentially claims that every time he thinks something in his mind, he has proof that he exists. It is not possible to think without also existing. With this ...

Vietnam War Escalation and Americanization

Vietnam War Escalation and Americanization The Vietnam war escalation began with the Gulf of Tonkin incident. On August 2, 1964, USS Maddox, an American destroyer, was attacked in the Gulf of Tonkin by three North Vietnamese torpedo boats while conducting an intelligence mission. A second attack seemed have occurred two days later, though the reports were sketchy (It now appears that there was no second attack). This second â€Å"attack† led to US air strikes against North Vietnam and the passage of the Southeast Asia (Gulf of Tonkin) Resolution by Congress. This resolution permitted the president to conduct military operations in the region without a formal declaration of war and became the legal justification for escalating the conflict. Bombing Begins In retribution for the incident in the Gulf of Tonkin, President Lyndon Johnson issued orders for the systematic bombing of North Vietnam, targeting its air defenses, industrial sites, and transportation infrastructure. Beginning on March 2, 1965, and known as Operation Rolling Thunder, the bombing campaign would last over three years and would drop an average of 800 tons of bombs a day on the north. To protect US air bases in South Vietnam, 3,500 Marines were deployed that same month, becoming the first ground forces committed to the conflict. Early Combat By April 1965, Johnson had sent the first 60,000 American troops to Vietnam. The number would escalate to 536,100 by the end of 1968. In the summer of 1965, under the command of General William Westmoreland, US forces executed their first major offensive operations against the Viet Cong and scored victories around Chu Lai (Operation Starlite) and in the Ia Drang Valley. This latter campaign was largely fought by the 1st Air Cavalry Division which pioneered the use of helicopters for high speed mobility on the battlefield. Learning from these defeats, the Viet Cong seldom again engaged American forces in conventional, pitched battles preferring instead to resort to hit and run attacks and ambushes. Over the next three years, American forces focused on searching and destroying Viet Cong and North Vietnamese units operating in the south. Frequently mounting large-scale sweeps such as Operations Attleboro, Cedar Falls, and Junction City, American and ARVN forces captured large amounts of weapons and supplies but rarely engaged large formations of the enemy. Political Situation in South Vietnam In Saigon, the political situation began to calm in 1967, with the rise of Nguyen Van Theiu to the head of the South Vietnamese government. Theiu’s ascent to the presidency stabilized the government and ended a long series of military juntas that had administered the country since Diem’s removal. Despite this, the Americanization of the war clearly showed that the South Vietnamese were incapable of defending the country on their own.

How to Hang in for the Long Haul

How to Hang in for the Long Haul Why do I love C. Hope Clark’s protagonist Carolina Slade? She’s relentless in the pursuit of truth. She steps around those who say â€Å"no.† She’s a maverick tuned straight into reality - a heroine with her feet in clay, not ether. Writers need this persistence. We shrug off rejection, doubt, and the unknown. This gig ain’t for flakes. Most days, nobody cares what you do. But anything worth doing plays Think about the Nobel Prize recipients in Physics. Englebert and Higgs discovered the Higgs-Boson, aka the God particle, in 1954. Fifty-nine years passed with no one knowing their names. What’d they do in the meantime? Kept working. Followed their passion. Writers in it for the long haul know work never stops; the mountaintop is never â€Å"achieved.† No matter who notices, we must love the invisible toil. In a culture where fans scream for blood after a few losses and ba When I began reading FundsforWriters, I had a pile of unknown stories and a novel languishing after 15 years. Hope’s words comforted me, as did leads from Poets Writers. I began submitting to contests and magazines. Every time I got a submission confirmation, I got a ping of validation. Since childhood I’ve read voraciously, so I made time for this love. I embarked on my personal MFA to study great writers, annotating religiously. Then I returned to my rough stuff, inspired. I found supportive writers’ groups. People said nice, tough things, motivating me to revise. In 2008 a small-circulation magazine accepted a story. Then in 2009, I won a contest. I spent the money on a laptop. This inspired me to start a novel about a teen girl obsessed with Michael Jackson. I got up mornings before work and in six months wrote a draft. I had no idea there would be 25 more. I continued to follow Hope’s journey. Through her I found Nathan Bransford’s and Rachelle Gardner’s blogs. I joined Querytracker. I began querying agents and after 150 emails, found one in 2011. I was a finalist for the James Jones Fellowship and denied a grant. I parted ways with my agent in 2012. I re-applied for the grant in 2012 and got it. (FundsforWriters lead!) Now I’ve published two books: a YA novel and a short-story collection. I have a beautiful website (thank you, Shaila Abdullah!). Check out my trailer, signings, and other news at lynhawks.com. I’ve learned to love The Slog this way: Subscribe to newsletters like FFW. Submit to publications, contests, and grants. Make deadlines and new drafts. Have a goal each day and week. Check off lists. See progress. Make sacred writing time. Defend it like your firstborn. Go for The Personal MFA. Revel in words. Talk to artists who celebrate ups and suffer downs. (I married a musician.) Keep your beloved pet near Find beta readers to keep your story alive. Celebrate what goes well, like the encouraging rejection. Give yourself a daily reward, like a lattà ©. (Caffeine Rewards Program) Find every way to fan the flames of writing love. Be a true fan of you. That’s how this writer does the long haul.

Effects of poverty on malaria in the rural areas of India Research Paper

Effects of poverty on malaria in the rural areas of India - Research Paper Example The approach of irrigation is causing desertification of the fertile land. There are huge investments made by the central and state government towards developing alleviation programs of poverty. Such an approach has not been able to make the rural areas self reliant but in turn has increased the economic dependency amongst the daily wage workers. In the urban areas there are preventive measures taken by the government so that such diseases do not affect public health but on the contrary the rural areas malaria is linked with poverty majorly due to lack of accessibility towards proper health care facilities and due to environmental degradation. The specific problem that has been identified in this particular context is that malaria is causing huge number of deaths in the rural India. Though the government is taking initiatives but it is not being able to safeguard people from such diseases. The problem area for this research study is that there needs to be proper measures implemented in rural India or else the rate of such disease would be high with every passing year. The major aim of the research study would be to highlight the relationship between the poverty and malaria and even to bring forward certain cases that would depict how some operations that are performed on rural land are leading to increase in the number of death rates caused by malaria. This research study would be important for the audience as it would portray the real scenario of rural India and even outline the major reasons behind why such a disease is not been able to eliminated from the area. The study would even help to analyze the direct relationship between poverty and malaria and the efforts that should be made so that such a disease can be discarded from the root level. The research question for this study would be – â€Å"How does poverty in rural India has a direct relation with the major public health disease malaria?† This research question is aligned with the

Art Paper 2 Essay Example | Topics and Well Written Essays - 1000 words

Art Paper 2 - Essay Example This was the same song that Whitney Houston had performed live in the 1989 Grammy Awards where she won the award for the â€Å"Best Female Pop Vocal Performance.† This song also topped charts in the US, UK, Australia, Germany and Switzerland for several consecutive weeks (NationMaster.com). The song "One Moment in Time" had aroused in me some sort of vigor after hearing it. I wondered, would everyone who had heard it so intently for the first time, had felt the same way as I did? Hearing it made me contemplate and thought about certain things about myself: have I reached my fullest potential yet? Am I already free--free from the notion of having been a victim of my fate? Can I say that I am a free person, a person who controls her own destiny? Then I thought, like every person in this world, I too should have that one moment in time when I am more than I thought I could be; I would have my one moment in time, and I should seize it. The moment I listened to the opening lines of the song, I knew it was the starting point of those who would look toward their quest to greatness. As the persona in the song sang the lines "Each day I live I want to be/ a day to give the best of me," I thought, in order for a person to live so enthusiastically each day of her life, it must be rooted in a single, ultimate purpose which had both driven the will to live and the will to succeed. Knowing a persons ultimate purpose for living would propel her to give her best each day in pursuit of such goal, and then, I knew that single purpose would be the start of everything for a person. Because of this singleness of purpose, the persona was driven to reach her ultimate goal, although the future seems uncertain. This was apparent in the lines "Im only one, but not alone/ My finest day is yet unknown." In reaching for ones goal, the persona knew that there would be obstacles to face, and that everything required trade off on her

The Chinese Communist Partys Ideological Change Essay

The Chinese Communist Partys Ideological Change - Essay Example There have been many changes in the political systems and in particular to the ideology of the Chinese Communist Party, from 1978, when the then leader of the party and the country Deng Xiaoping began to initiate reforms and a movement towards a more market oriented economy. According to Misra (1998, p.272) and other scholars predicted the imminent decline and demise of the Marxist ideology in China, while other scholars who held a contrary opinion held that the ideology is not on its death bed; rather it is on its path to recovery (Brugger and David 1990, p.7). Ordinary Chinese citizens had become tired with the ideologies of the party and those of the its high profile leaders, it was perceived by the masses as more of a privileged society but less in touch with what is happening on the ground, this majorly began in the late 1990s. Currently, there is a general feeling amongst the populace that the Chinese Communist Party is riddled with corruption, and its sheer size complicates ef fectiveness of the party. Pro-democracy scholars and activist have a firm belief that the Party has lost its relevance in this century, and that the current leaders have lost legitimacy from the people and that they suffer from governance issues and this will ultimately lead to its collapse. After the death of the Chinese leader, Deng in 1997, majority of leaders in the west and particularly the United States predicted the collapse and adoption of ideologies of democracy in China. Most of them had predicted in the late 1990s that the regime would eventually collapse in the year 2010; this has happened, as the current leader is tightening these political policies but opening up the economy. In the

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

Global Financial Management - Essay Example nations have different practices and foreign policies, Ghosn encouraged the building of new production plants across different countries to cut on the costs. Foreign currencies often caused price fluctuations for Nissan Company; production of its equipment and motor vehicles in yen made it vulnerable to fluctuation problem. This is because not all of its foreign customers made their purchases at the same exchange value. Carlos studied the problem and established that the starting of new assembling plants in the foreign countries would save the company from unnecessary costs (Heidrich, 2007). Further, he set a program that would weigh the commodity costs over to the foreign currencies such that Nissan would not entirely bid. It defined its investment into short-term and long-term ones, thus, coming up with definite objectives activities of core interest. To reduce the entire production cost of its vehicles, CEO encouraged to source spares from suppliers; this reduced the costs of employees and further shifted the risks to the suppliers accordingly. However, the practice did not affect much on the commodity cost reduction. Therefore, Nissan set an approach to technological advancements; eventually, this would help to minimize usage of expensive raw materials. The exercise has proved to bring useful increment in profits over the past financial periods. Nissan directly employs a cost shifting policy whereby all costs are periodically set such that whenever there are no changes in the selling price, there are no changes in the purchasing price. The concept that risks exposed Nissan to conflicts of exchange elevates the meaning that it employs measures to maintain interests and put lesser concerns on profitability. Nissan Company merges relatively comfortably with the entire business community. The effective, harmonious environment it poses to its employees facilitates it; company affiliates, for example, Mercedes Benz and Renault, set it above par (Heidrich, 2007).

Community Health Promotion Tool Assignment Example | Topics and Well Written Essays - 500 words

Community Health Promotion Tool - Assignment Example There are populations that are at risk of getting the heart disease quickly which are male with a history of the heart disease in their family as well as increase in age. Older people are at high risk of getting the disease than the younger population (Topol and Califf, 2007). The population being targeted by this summary research is the African American male over the age of 65 years as they are the ones whose death statistics from the coronary heart diseases has been on the increase in the last decade. This population is at risk because of their gender, their race, and lack of physical activities, unhealthy eating habits, their high blood pressure and above all their high increase in diabetes (Topol and Califf, 2007). The African American male at this age of over 65 years believe themselves to be invincible to any health problems and they therefore engage in reckless eating habits. They already have their families and hence are not looking out to improve their appearance or impress the females by going to the gym and exercising as is the norm with the younger generation. This population at this age has children who are in their mid-twenties and thirties and most of them are not turning out the way they are supposed to. For elderly male whose children have retorted to crime and prostitution and others who have neglected their parental duties, their high blood pressure seems to be on the increase ever. With the increased high blood pressure combined with diabetes from the bad healthy choices combine with reckless eating habits and lack of exercise, these population develops the coronary heart disease faster than any other population group and it kills them faster as well. Their cultural beliefs do not pay special attention to seeking constant medical attention as prevention techniques or carrying out regular medical

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

Global Financial Management - Essay Example nations have different practices and foreign policies, Ghosn encouraged the building of new production plants across different countries to cut on the costs. Foreign currencies often caused price fluctuations for Nissan Company; production of its equipment and motor vehicles in yen made it vulnerable to fluctuation problem. This is because not all of its foreign customers made their purchases at the same exchange value. Carlos studied the problem and established that the starting of new assembling plants in the foreign countries would save the company from unnecessary costs (Heidrich, 2007). Further, he set a program that would weigh the commodity costs over to the foreign currencies such that Nissan would not entirely bid. It defined its investment into short-term and long-term ones, thus, coming up with definite objectives activities of core interest. To reduce the entire production cost of its vehicles, CEO encouraged to source spares from suppliers; this reduced the costs of employees and further shifted the risks to the suppliers accordingly. However, the practice did not affect much on the commodity cost reduction. Therefore, Nissan set an approach to technological advancements; eventually, this would help to minimize usage of expensive raw materials. The exercise has proved to bring useful increment in profits over the past financial periods. Nissan directly employs a cost shifting policy whereby all costs are periodically set such that whenever there are no changes in the selling price, there are no changes in the purchasing price. The concept that risks exposed Nissan to conflicts of exchange elevates the meaning that it employs measures to maintain interests and put lesser concerns on profitability. Nissan Company merges relatively comfortably with the entire business community. The effective, harmonious environment it poses to its employees facilitates it; company affiliates, for example, Mercedes Benz and Renault, set it above par (Heidrich, 2007).

Paper on Three Kingdoms by Luo Guanzhong Essay Example | Topics and Well Written Essays - 1250 words

Paper on Three Kingdoms by Luo Guanzhong - Essay Example War breaks out because of questions regarding the legitimacy of succession. As a consequence China subdivides into three major branches with Cao Cao reigning in the north, Sun Quan ruling in the south, and Liu Bei controlling the west sector of China. The Romance of Three Kingdoms by Luo Guanzhong is a classic historical novel dealing with the power struggles within the Han dynasty which inevitably precipitate its collapse. An intricately woven book integrating historical accurate events merged with creative fiction, this book centers on themes such as brotherhood, art of war and religion.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  This novel also weaves in elements of Confucianism whose doctrines are based principally on The Mandate of Heaven. The Mandate of Heaven marks the transition from the Shang dynasty (1766-1122 BCE) to the Zhou dynasty (1122-256 BCE) violation of the macrocosmic concepts: through corruption, immortality, and misrule led to Shang's deposition from power by the Zhou Dynasty, Hea ven reserved the right to interpose in the microcosm especially when discord threatens. Political corruption made the emperor, also called the son of heaven unfit to rule therefore, the Mandate of Heaven can be legally transferred to another who was better and morally qualified. The Mandate of Heaven encapsulates the main principles of principles of Confucianism : ren (benevolence), xiao (filial piety), and li(propriety and convention), which secured harmony and equilibrium with the macrocosms (nature and heaven) and the microcosm (man's affairs). It is through application of the principle of the Mandate of Heaven that the Han dynasty is overthrown. Zhang Jiao was the catalyst in the Yellow Turban Rebellion in 184 A.D. Jiao began the revolution to undermine and collapse the Han Dynasty due to social injustices experienced by citizens.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Daoism constitutes a large part of the novel since its ideals and teachings are practiced by the characters of The Romance of Three Kingdoms. Daoism is a pacific religion which stands for order and harmony with nature and with man. This concept is mirrored in the affirmation that that state of being "in accord with nature is (being) in accord with Dao." There exist compatibility, coexistence and harmony with opposite natures and this relation is called harmonious dualism. Zhuge Liang is an educated Taoist scholar who personifies some of the principles of Daoism. Dao which is "divine and everlasting" means "the way of nature and the cosmos" thus one sees the bond between the universe and man. Zhuge acts as an emissary, diplomat and successful martial strategist to Sun Quan.   Zhuge Liang, as a Daoist peacekeeper, pacifies several warlords in the South, at the same time, he spearheads the Shu Han forces on expeditions to strengthen the Han empire. He never dies on the battle field but succumbs to tubercolosis. Zhuge Liang's strategies always triumphs as he continually foils the plans of his adversaries.   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  The Romance of Three Kingdoms incorporates tenets from another Chinese classical text, The Art of War written by Sun Tzu, a notable Chinese general who explains the importance of the war to the state and gives pithy advice on martial techniques on how to maneuver one's army to secure victory. The Battle of Xiaoting, the Battle of Red Cliffs and the Battle of Wuzhang Plains are noteworthy collisions in the novel in which various arts of war are implemented. Lu Bu observes that "Cao Cao knows something of the art of war" (Guanzhong 90). In the Art of War, moral

Planning and implementing classroom meetings Essay Example for Free

Planning and implementing classroom meetings Essay Class room meetings do provide a perfect forum for the establishment of a conducive learning environment in the school scenario. It does give the learners a perfect environment for them to practice their communication and socialization skills which are in cooperated in the teaching curriculum. The class meetings are meant to serve some purposes which are listed below. Purpose of the class meetings: The main purpose or major aim for class meetings is to try and resolve some key discipline problems that are encountered in the learning environment. The class meetings do therefore create the required environment for the teacher and learners to work together in trying to resolve some problems that are always encountered in the school scenario for example discipline problems whereby learners harass other learners in class or during play time, making noise that disturbs the learning environment negatively and other incidents. Through the class meetings, an approach is created whereby the teacher and the learners try to resolve the first few incidents of misbehavior before they do get out of hand. An example of a minor conflict that can get out of hand and become a major full scale discipline problem is the case whereby a given learner is constantly being bullied by other learners who happen to have bigger and stronger bodies as compared to him/her. If this kind of vice continues for some time then it is likely to lead that particular learner to a state of being depressed and feeling unwanted in that environment. Once the learner enters the state of being depressed then he/she is likely to start using drugs to escape the state of depression and sometimes it can lead the learner to dropping out of school. Therefore, when a meeting is held in the class, it serves a purpose of trying to guide and counsel the learners to avoid such vices and treat each other fairly with some equity in order to create a more conducive environment for learning. The class meetings do also serve a purpose of facilitating and creating a positive relationship in the learning environment. The meetings provide an opportunity for the learners and the teachers to be able to build some form of trust, respect and confidence in each other which leads to the creation of a warm and caring environment. The confidence created by the class meetings leads to the creation of an environment that is full of mutual understanding thereby enabling all the class members to make statements or state opinions freely without feeling unsecure. Classroom meetings do develop closer relationships between the learners and even between the learners and their teachers. This closer relationships come when the learners are discussing issues or are having conversations in a relaxed manner whereby they do talk of where they come from, about their families and there general background. This relationships end up creating a class that is manageable since the involved parties do get to know and understand each other accordingly. A good example is when a teacher holds a meeting with her kindergarten learners; at first the children are not so free with the teacher. They tend to create and keep a certain distance between them and the teacher. A teacher may ask them to respond to some question but they choose to be quiet and not that they do not know the response, but they could not be free with the teacher. But if she holds some meetings with them whereby she addresses them warmly then she is bound to break the communication barrier between her and the young learners. This ends up creating a relationship of mutual benefit between the learners and the teacher. (Marshal 2001). Through class meetings, learners do acquire important development skills. The skills include the ability to listen attentively and to have an understanding of each other. As the class meetings go on, learners discover that if they do not pay attention or listen carefully and attentively to what the others are saying, then they are meant to lose some key interesting points and some humorous contributions. ( Marshall 2001). Class meetings also have a purpose in enabling the learners to develop other skill for example reflecting listening whereby a learner is supposed to paraphrase what he/she had heard earlier on from a classmate. This skill enables the learner to listen with some form of understanding. A reflective dialogue also enables the learner to develop a clear and concise speech which is an important element in the art of communication. It enables the learner to know that if there speech is not clear then there point may not be understood properly or clearly and therefore they won’t be able to make their point or view known (Marshall 2001). Learners gain skills that enable them to be team players. When they are holding discussions in the class meetings, the various opinions that they give from their point of view and contributions that they make helps them in cultivating the team spirits. Objectives of class meetings. Classroom meetings do have some objectives that serve to improve the life of the learners and teachers in the learning environment. The objectives are meant to: Improve the general communication skills of the learners. The communication skills include the listening and speaking skills. When the learners are participating in the discussion of issues that affect them in school they not only nurture their speaking skills but also their listening skills which are an integral component in the learning environment. The listening skills enable the learners to pay close attention to what the others in class are trying to communicate. Provide opportunities for the learners to develop skills for insightful, creative and critical speaking (Marshall 2001). Classroom meetings provide a platform that enables learners to practice their speaking skills. When the learners are engaged in debates during the class meetings or when they are asked by the teacher to give their own views on some given issues, it does give them that opportunity that enables them to improve and even cultivate better speaking skills. Their creativity is improved when they are asked to give solutions and provide a way forward for some critical issues that affect their well-being in school. Create an opportunity for the learners to interact respectfully and promote their team work spirit. The interaction with each other in class meetings enables the learners to understand each other from all perspectives. Team work spirit enables them to be team players and to work together in resolving any problems and miss-understandings that they face not only in school but also in the outside world also where they meet bigger and tougher challenges. Foster social skills for example reducing shyness (Marshall 2001). Classroom meetings enable learners to interact positively through participating in conversations and debates in class which enable them to overcome their shyness as they become more confident in holding discussions. The more the learners participate in class meetings, the more they overcome their shyness. Classroom meetings build a trusting and caring relationship between the learner and the teacher. When the teacher holds a meeting to discuss with the learner issues that do affect them in a friendly way them the relationship between the teacher and the learner is bound to improve. The learners will free being with that teacher which is a necessary requirement for the learning process to be more effective. The learners will be free to ask the teacher any question which they do not understand and in turn the teacher will do what is required of him/her professionally. Agenda of classroom meetings. Agenda, from the view of class meetings is a term meant to refer to the different matters that affect the learners and are meant to be solved during meetings through giving suggestions, discussing them or using any other appropriate way to solve them. Class meetings are designed in such a way that they try to improve the learning environment and change it positively beginning with the students themselves. Teachers have their own agendas for classroom, for example the teachers use the meetings to gain some instructional objectives from the learners (Marshall 2001). Instructional objectives are obtained when the teacher asks the learners questions that pertain the class meeting or the lessons held in class. For example the teacher can ask the learners to give suggestions on how they could make the next lesson better than the present one. It gives the learners the opportunity to reflect in their minds and try to give suggestions that will help improve the next lesson. This kind of reflection also helps those kids who easily switch of from the current events to other ones that are not part of the class meetings. When they are asked to give suggestion concerning the betterment of the meeting then they are likely to linger on when that lesson or meeting is held since they gave a suggestion concerning it. Teachers can also have other agendas like setting up the tone of a class for learning. This is particularly an important agenda especially when a given class is a very difficult class to manage for example a class that is full of mischief from the learners. If a class meeting is held at the beginning of the learning process, then the teacher might be successful in implementing some rules that will be used through the learning exercise and set the right tone for the learning process from the beginning of that session to the very end (Marshall 2001). Having Class meetings can also have agendas that involve learners discussing on the right approach for them to use in doing their assignments and in reviewing them. For example they can discuss whether it is appropriate for them to hold discussions as a whole class in order to do review an assignment that they had done earlier on or it will be appropriate for them to do the assignments in smaller groups or it will be more appropriate for them to do them individually through research. Such an agenda enables the learners to find a better way of handling their class work, a way that will benefit them more. They also get to give reasons why they think a given approach will benefit them more than the other approaches. Also in the class meeting agenda, the way of dealing with minor problems should be spoken about or discussed. Dealing with class room misbehaviors should be an agenda. In some cases, especially when dealing with young learners of lower classes, a teacher gets complaints like â€Å"teacher this one is squeezing my hand†. Both the learners and the teacher should agree on what to do during such incidents. When the learners decide for themselves, it becomes a sure way of controlling some vices in the class room as they will be conscious of what they will be doing in class and will obviously try as much as possible to avoid getting into trouble. Formulating questions. The purpose, objectives and goals of the meeting should be clear to the teacher in order to enable him/her to formulate the right kind of questions that will enable him/her to achieve all the goals of the meetings. The teacher must formulate open ended questions. Open ended questions invite a discussion and are the best when holding a class meeting as they require more than just an answer. They let the learners to give explanations as to why they feel as they feel. (Marshall 2001). Closed ended questions are those that require simple answers only. They do not elicit any explanations from the learners. They require a yes or no answer. Such questions should be avoided at all times. They do not even play a simple role of nurturing the creativity of the learners. The open ended questions help a lot in improving the creativity of the learners as they give room for the learners to think widely and try to come up with the right solutions or answer to a given problem. The teacher should therefore formulate open-ended questions. An example of open ended questions is a question that begins with â€Å"Why? † or â€Å"How? †. This way, a justification is given by the student and at the end does show that the student did do some thinking or reasoning. The teacher should also formulate questions that seek for clarification. A learner should try to explain the reasons why they chose on a given answer. In other words, the learner should not only give a flat answer but also explain that answer and try to clarify it more. Some learners have a tendency of letting their minds wonder far off from the events that are currently taking place in class and once they are asked to answer a given question they ask their neighbors in class and give an answer that serves the purpose of redeeming them from some shame. If a teacher formulates questions that seek clarification then the learner’s attention will most likely be captured to end of the meeting. Length, time and frequency Length, time and frequency of a class meeting depends on the class and age of the learners, the nature of that group, the kind of interests that they have during the meetings and the type or nature of topic that is being discussed. Meetings for young children, for example those in kindergarten should be planned and held for around ten minutes while the one for older learners i. e. those in higher classes can be held for a longer time, about twenty minutes. (Marshall 2001). The meetings should always be held at the same time as planned or as in schedule. For example, some teachers do hold meetings before the class breaks for lunch, at the end of the period or when the day ends. Teachers, who handle middle and high school classes, hold meetings at the beginning of every class in order to discuss how the learners are faring on and to check on the progress of the class projects. These meetings that are held at the beginning of the class in co-operate the learners into the planning process which leads to increase in the learning processes even though only a few minutes are spared for a discussion. According to Marshall, the elementary classes should hold meetings on a daily basis as a way of keeping them in track. It checks on their behavior and if they are doing what they are supposed to do in school. Marshall also argues that if the middle and high school classes do not hold meetings on a regular basis then they will be depriving themselves of the so many advantages that do come with the meetings when they are held regularly. Physical environment. The physical environment should be created in a satisfactory manner. The kind of physical environment created should guarantee the meeting some quality. For example if a teacher decides to create a circle or to adopt a circle format for the meeting, then it is obvious that the meeting will have a high quality attached to it since the learners see each other face to face and are therefore able to read each other’s expressions as well as hear the words that are being spoken in a better way as compared to them being seated in rows and facing the teacher whereby the learners won’t be able to see the ones who are contributing from the back of the class (Marshall 2001) When the learners are seated in rows, they will squirm around to see the person contributing from the back. This leads to lack of concentration that is a necessity in the discussion. Therefore, teachers should adopt an environment that is more effective for the discussion to be of a greater success. A circle format for the sitting arrangement is the best for holding class meetings. Furniture. Desks are a barrier to open discussions in class. They should be moved in order to pave way for a circle. The learners should only use their chairs if the meeting is to be more effective. For the younger learners, those in lower grades, sitting on the floor will be more effective in that movement will be minimal from them. It will also save time for moving desks and chairs since they are young and do not know the value of time. (Marshall 2001). Role of the teacher. The major role of the teacher is to facilitate the meeting. For example, the teacher has to monitor the learners, pose the right questions and give the right answers to the learners. The teacher has to ensure that the right comments are made to every student who attempts to bring something into the discussion. If a teacher comments on only one learner’s contribution and ignores the other, then that student is bound to believe that his contribution was not worthwhile. The teacher has to conclude the meeting. He/she has to summarize all the points that have been discussed and to make sure that all the learners understand all that has been discussed. Role of the student. The student plays a role in implementing what has been discussed and agreed upon. If the meeting set an agenda on keeping silence in class, then the learner has to try and be silent. If they agreed on how cleaning of classrooms should be done then the learner has a role to play to make sure that all is a success. Closing the meeting. The teacher should give a summary of the whole meeting on what has been agreed upon. The teacher could also draw a consensus or just state the agreed solution in a problem solving meeting. It serves to reinforce the discussions of the meeting. Evaluation. At the end of the meeting, the teacher should ask himself or herself some questions that reflect on the meeting and are meant to improve skills. For example: are the learners expressing their own opinions? Are the students displaying any evidence of insightful thinking? (Marshall 2001). The teacher can also asses the level of participation of the learners i. e. if they all took part in the discussion. In conclusion, class meetings are an important part in the creation of a conducive learning environment. When meetings are held with the learners, they not only check on the behavior of the learners but also improve the relationship of the learners and the teacher which is an important aspect in the teacher student relationship. References. Marshall, M. (2001). Classroom meetings. .New York: Piper Press.

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