Malaysian Financial Reporting Standard 116 Essay

Malaysian Financial Reporting Standard 116 Property, Plant and Equipment This form incorporates corrections coming about because of MFRSs with compelling dates no later than 1 January 2012. Revisions with a compelling date later than 1 January 2012 MFRS 116 has been changed by MFRS 13 Fair Value Measurement*. As those corrections have a compelling date after 1 January 2012 they are excluded from this version. * powerful date 1 January 2013 559 MFRS 116 Substance passages Preface INTRODUCTION IN1â€IN15 MALAYSIAN FINANCIAL REPORTING STANDARD 116 PROPERTY, PLANT AND EQUIPMENT OBJECTIVE SCOPE DEFINITIONS RECOGNITION Initial costs Subsequent costs MEASUREMENT AT RECOGNITION Elements of cost Measurement of cost MEASUREMENT AFTER RECOGNITION Cost model Revaluation model Depreciation Depreciable sum and devaluation period Depreciation technique Impairment Compensation for disability DERECOGNITION DISCLOSURE TRANSITIONAL PROVISIONS EFFECTIVE DATE WITHDRAWAL OF OTHER PRONOUNCEMENTS 1 2â€5 6 7â€14 11 12â€14 15â€28 16â€22 23â€28 29â€66 30 31â€42 43â€62 50â€59 60â€62 63 65â€66 67â€72 73â€79 80 81â€81E 82â€83 560  © IFRS Foundation MFRS 116 Malaysian Financial Reporting Standard 116 Property, Plant and Equipment (MFRS 116) is set out in sections 1â€83. All the passages have equivalent position. MFRS 116 ought to be perused with regards to its target and the Basis for Conclusions, the Foreword to Financial Reporting Standards and the Conceptual Framework for Financial Reporting. MFRS 108 Accounting Policies, Changes in Accounting Estimates and Errors gives a premise to choosing and applying bookkeeping strategies without unequivocal direction.  © IFRS Foundation 561 MFRS 116 Introduction The Malaysian Accounting Standards Board (MASB) is actualizing its strategy of combination through receiving International Financial Reporting Standards (IFRSs) as gave by the International Accounting Standards Board (IASB) for application for yearly periods starting on or after 1 January 2012. The IASB characterizes IFRSs as involving: (an) International Financial Reporting Standards; (b) International Accounting Standards; (c) IFRIC Interpretations; and (d) SIC Interpretations. Malaysian Financial Reporting Standards (MFRSs) identical to IFRSs that apply to any detailing period starting on or after 1 January 2012 are: (a) Malaysian Financial Reporting Standards; and (b) IC Interpretations. First-time use of MFRSs proportionate to IFRSs Application of this Standard will start in the first-run through adopter’s * first yearly announcing period starting on or after 1 January 2012 in the contextâ of embracing MFRSs identical to IFRSs. For this situation, the necessities of MFRS 1 First-time Adoption of Malaysian Financial Reporting Standards must be watched. Utilization of MFRS 1 is important as in any case such budget summaries won't have the option to state consistence with IFRS. MFRS 1, what could be compared to IFRS 1 First-time Adoption of International Financial Reporting Standards, requires earlier period data, introduced as relative data, to be rehashed as though the prerequisites of MFRSs successful for yearly period starting on or after 1 January 2012 have consistently been applied, aside from when it (1) denies review application in certain angles or (2) permits the first-run through adopter to utilize at least one of the exclusio ns or special cases contained in that. This implies, in setting up its first MFRS money related statements* for a monetary period starting on or after 1 January 2012, the first-run through adopter will allude to the arrangements contained in MFRS 1 on issues identifying with change and viable dates rather than the transitional arrangement and compelling date contained in the particular MFRSs. This contrasts from past necessities where an element represented changes of bookkeeping approaches as per the particular transitional arrangements contained in the separate Financial Reporting Standards (FRSs) or as per FRS 108 Accounting Policies, Changes in Accounting Estimates and Errors when the FRS did exclude explicit transitional arrangements. * Addendum An of MFRS 1 characterizes first-time adopter and first MFRS fiscal summaries. 562 MFRS 116 in such manner the viable and issuance dates contained in this Standard are those of the IASB’s and are inapplicable in the new MFRS structure since MFRS 1 prerequisites will be applied on 1 January 2012. Correlation and consistence with IAS 16 MFRS 116 is proportionate to IAS 16 Property, Plant and Equipment as gave and altered by the IASB, including the compelling and issuance dates. Elements that follow MFRS 116 willâ simultaneously be in consistence with IAS 16. 563 MFRS 116 Presentation IN1 International Accounting Standard 16 Property, Plant and Equipment (IAS 16) replaces IAS 16 Property, Plant and Equipment (reexamined in 1998), and ought to be applied for yearly periods starting on or after 1 January 2005. Prior application is supported. The Standard additionally replaces the accompanying Interpretations: ï‚ · SIC-6 Costs of Modifying Existing Software SIC-14 Property, Plant and Equipmentâ€Compensation for the Impairment or Loss of Items SIC-23 Property, Plant and Equipmentâ€Major Inspection or Overhaul Costs. IASB’s explanations behind reexamining IAS 16 IN2 The International Accounting Standards Board built up this changed IAS 16 as a major aspect of its undertaking on Improvements to International Accounting Standards. The task was attempted in the light of questions and reactions brought up according to the Standards by protections controllers, proficient bookkeepers and other invested individuals. The goals of the undertaking were to decrease or dispense with options, redundancies and clashes inside the Standards, to manage some intermingling issues and to make different upgrades. For IAS 16 the IASB’s primary target was a constrained amendment to give extra direction and explanation on chose matters. The IASB didn't rethink the crucial way to deal with the representing property, plant and gear contained in IAS 16. IN3 The principle changes of IAS 16 IN4 The fundamental changes from the past form of IAS 16 are depicted underneath. Extension IN5 This Standard explains that an element is required to apply the standards of this Standard to things of property, plant and hardware used to create or keep up (an) organic resources and (b) mineral rights and mineral saves, for example, oil, flammable gas and comparable non-regenerative assets. Acknowledgment: resulting costs IN6 A substance assesses under the general acknowledgment guideline all property, plant and hardware costs at the time they are brought about. Those expenses incorporate expenses caused at first to secure or build a thing of property, plant and gear and expenses brought about along these lines to add to, supplant some portion of, or administration a thing. The past variant of IAS 16 contained two acknowledgment standards. A substance applied the second acknowledgment rule to resulting costs.  © 564 IFRS Foundation MFRS 116 Estimation at acknowledgment: resource disassembly, evacuation and reclamation costs IN7 The expense of a thing of property, plant and gear incorporates the expenses of its disassembly, expulsion or rebuilding, the commitment for which an element brings about as a result of introducing the thing. Its expense likewise incorporates the expenses of its disassembly, expulsion or reclamation, the commitment for which a substance brings about as an outcome of utilizing the thing during a specific period for purposes other than to deliver inventories during that period. The past rendition of IAS 16 included inside its extension just the expenses acquired as an outcome of introducing the thing. Estimation at acknowledgment: resource trade exchanges IN8 An element is required to gauge a thing of property, plant and gear gained in return for a non-fiscal resource or resources, or a mix of money related and non-financial resources, at reasonable worth except if the exchangeâ transaction needs business substance. Under the past form of IAS 16, an element estimated such a procured resource at reasonable worth except if the traded resources were comparable. Estimation after acknowledgment: revaluation model IN9 If reasonable worth can be estimated dependably, a substance may convey all things of property, plant and gear of a class at a revalued sum, which is the reasonable estimation of the things at the date of the revaluation less any ensuing collected devaluation and amassed weakness misfortunes. Under the past variant of IAS 16, utilization of revalued sums didn't rely upon whether reasonable qualities were dependably quantifiable. Deterioration: unit of measure IN10 A substance is required to decide the devaluation charge independently for each critical piece of a thing of property, plant and hardware. The past variant of IAS 16 didn't as unmistakably set out this necessity. Deterioration: depreciable amount IN11 A substance is required to gauge the leftover estimation of a thing of property, plant and gear as the sum it gauges it would get right now for the advantage if the benefit were at that point of the age and in the condition expected toward the finish of its valuable life. The past adaptation of IAS 16 didn't indicate whether the remaining worth was to be this sum or the sum, comprehensive of the impacts of expansion, that an element expected to get later on the asset’s genuine retirement date. Deterioration: devaluation period IN12 A substance is required to start devaluing a thing of property, plant and hardware when it is accessible for use and to keep deteriorating it until it  © IFRS Foundation 565 MFRS 116 is derecognised, regardless of whether during that period the thing is inactive. The past rendition of IAS 16 didn't determine when deterioration of a thing started and indicated

Trip to Tadoba Tiger Reserve Free Essays

string(121) By this time we likewise discovered that the Hyderabad bunch had run into substantial downpours and awful climate prompting moderate progress. CITY TIGERS MEETING THEIR COUNTRY COUSIN This meet started with me and my sibling continuing to Mumbai air terminal for our first trip to the orange city Nagpur. Not long after looking into the flight we got with group bhpian and member in the workshop (sachin. sri) Sachin Shrivastava. We will compose a custom paper test on Excursion to Tadoba Tiger Reserve or on the other hand any comparative subject just for you Request Now He was at that point in the city on authentic work and we found our particular advantages on the gathering. We had a smooth flight and as guided by Dr. Abheek via telephone we met our taxi come to get us from the air terminal. We found that it was sprinkling in Nagpur and this hosed our spirits a piece imagining that natural life spotting would be troublesome in relentless downpour. We continued to the beginning stage where we were to meet different members from Nagpur. The fact of the matter was Hotel Turning Point at Laxmi Chowk. Here Wild Cats part Mr. Sachet and the proprietor of Turning Point Mr. Amol welcomed us heartily. Mr. Amol offered us a rich breakfast and some fascinating stories of untamed life with regards to the edges of Nagpur. Exceptionally soon another Wild Cat part Mr. Chinmay Deshpande went along with us. Strangely he was a functioning snake rescuer for Nagpur and he had a bagful of snakes to be discharged in the wild during our excursion. Sachin was frightened and somewhat frightened by the nearness of such huge numbers of venomous and non-venomous snakes around. We were astonished and energized and attempt to console Sachin. We had just because such a nearby experience with snakes. Under the nearby direction of Chinmay we were even ready to deal with a non-venomous snake the knickknack snake without any problem. It was so excellent to hold the snake. In our grasp the snake appeared to be a velvet rope. It is extremely tragic that even before thinking a lot about snakes I had a biased dread of such wonderful animals. Chinmay appropriately clarified that snakes have no feeling and in the event that we people keep up our separation and exercise alert and satisfactory precautionary measure while collaborating with them there is no motivation behind why we can't exist together with the most venomous of snakes. Having said that he additionally clarified that the most experienced of handlers have been nibbled distinctly by either their lack of regard or carelessness. In a matter of moments Doc. (Dr. Abheek Ghosh) flew in. True to form he was a heap of vitality and energized the effectively energized pack. Meeting him just because I need to state the mustache suits him well, similar to the bristles of a wildcat. He had some news. The group from Hyderabad had missed their overnight train and had since continued via vehicle. They would meet us straightforwardly at Tadoba. One more of the organizer Mr. Akash Kothe likewise went along with us. We all wrapped up the morning meal meet and continued to our mentor, which was with us for the whole outing. The mentor had a standard of Wild Cats in the front, which was looking extremely adept for the event. As we were getting into the mentor we could see our host Amol likewise getting into the state of mind and needing to go along with us for the excursion. Anyway as had some unavoidable work in the city he was unable to go along with us. We bade him farewell and continued to Tadoba. Sachin was getting apprehensive with such huge numbers of snakes going along with us in the mentor albeit secure in their individual containers. We as a whole kidded this would be â€Å"SNAKES IN THE COACH† Indian variant of the well known Hollywood movie† SNAKES IN THE PLANE†. This made Sachin even more anxious and he attempted to make himself agreeable as distant from the snakes as could be expected under the circumstances. In any case, at each jolt and each pothole he would argue Chinmay to check if all the snakes were secure. The whole excursion of around 5 hours because of terrible streets after Jam was not really felt due the constant talk among us all. It was surprising that inspite of our changing foundations and ages we as a whole gelled in the blink of an eye. This goes to shows that eagerness is irresistible and knows no boundary. In the mentor Doc offered us an Audio Video narrative by Vidya Atreya on creature human clash in Western Maharashtra and how it was influencing the panther specifically. I had just perused up some material on her work and research as sent to us before by Doc. Doc additionally enlighted us on the work done by her on preservation and human panther peace promotion. We were so fascinated in our conversations and running low on time that we had skirted stopping for lunch anyplace enroute. As we approached crossed Chandrapur we were disheartened to see quarries for coal mining all around with gigantic stacks of spent mud lying all around like little slopes. Doc educated us that in spite of the fact that Chandrapur was one of the most dirtied regions of our nation due to the coalmines and warm plants the tigers were flourishing in the backwoods of Tadoba. We arrived at the Moharli Gate of Tadoba haven at the stroke of four, which was additionally the end time for section into the asylum. At the entryway the wanderers were prepared sitting tight for us as masterminded by Doc. Here we likewise met another of Doc’s dear companions Mr. Indraneel Pal and his companion Gaurav. Indraneel Pal was by calling a temporary worker for the Cement Mills around however by heart he was an ardent creature sweetheart. His top to bottom information on creature conduct by and large and the tiger specifically was surprising. We discovered that he was an ordinary guest to Tadoba, at times 2-3 times each week. He was to Tadoba what Doc is to Pench. Doc had a brilliant affinity with him and he also greeted us wholeheartedly. I was struck by his quietude and enthusiasm towards the backwoods and its occupants. It was an incredible delight and benefit to go through two days in his organization. At this point we likewise discovered that the Hyderabad bunch had run into overwhelming downpours and terrible climate prompting moderate advancement. You read Excursion to Tadoba Tiger Reserve in class Papers Enroute an area of the expressway was washed away and they were confronting a barricade in the alternate route because of some vehicle breakdown. In light of current circumstances they would not have the option to make it to Tadoba before dusk. All of us choose to continue for the night Safari. The sights and hints of the backwoods agreeably astonished city inhabitants like us. Tadoba is known to all, for the solid populace of tigers inside it yet it was additionally extremely fascinating to watch the wide assortment of flying creatures and bugs inside the save. Photographs will recount to the story here. We quickly detected a little crowd of sambar deer and a lone wild pig. In some time we arrived at the center (hattori) door. As required section conventions were being done, Doc asked his man Friday (Sanjay) to serve poha bundles to us all. At this point our stomachs had started thundering due go hunger having skipped lunch before. The poha was tasty and warm in the foil pack. Evidently doc had made some calls from the mentor as we were approaching Tadoba. Indraneel happened to reveal to us that in the first part of the day similarly as he entered the hold he recognized a panther near the passageway door. This elevated the fervor for us. He and doc disclosed to us that enormous predators like the tiger consistently mark the limits of their domain to feature their essence to their adversaries and console the females. What's more, during rainstorm because of washing endlessly of their fragrance markings by the downpour, they need to continue checking all the more often and because of which the odds of detecting the tiger is better. Both he and doc were very tuned to the different hints of the wilderness and could promptly make us aware of calls made by the sambar and a few winged creatures as they imparted to pass on the development of the tiger/panther. This gave us some sign of the development of these predators a good ways off. It additionally gave us a thought with respect to how troublesome it was for these predators to chase when their essence could be effectively parted with by the alert call of the langur, a fowl or some deer. In these environmental factors we effectively lost feeling of time. Very soon it was getting dull and the guide educated us that the time had come to go to the exit. We were starting to appreciate the experience and began to head back with crushing sadness. At that point the wanderer we were voyaging unexpectedly separated. We got enchanted reasoning this gave us an ideal reason to legitimize our postponement to the leave door and experience the sunset in the backwoods. In any case, this joy didn't keep going long as soon another vagabond of our gathering that went along gave us a lift to the center (Hattori) entryway. Now Doc â€Å"insisted† on remaining with the separated vagabond and it’s driver till it could be brought till the leave point. We all wished to assume Doc’s position so we could likewise encounter some piece of the night in the wilderness, yet it was not to be. We wished Doc karma and continued to the Hattori Gate. There the authorities were miffed with us for the postponement. On learning of the breakdown they offered a stopgap towrope and sent this vagabond back to tow our separated tramp. Doc more likely than not reviled his karma to see help coming so quick. When the tramp was towed into the Hattori door we continued to the Moharli leave entryway. Enroute we were trusting that the towrope snaps and we get postponed further. In any case, oh none of that occurred. In some time we arrived at the leave entryway. The authorities here were exceptionally disturbed, as we had shown up route past the end time. Fortunately Doc and Indraneel being regulars there by one way or another figured out how to appease them, yet brought to the table some composed clarification and pay some fine. We went to the MTDC resort with such a large number of stories to reveal to one another. In transit Chinmay disclosed to us that once we sink into our rooms we have to take care of the cobra on a frog, which could be effortlessly observed croaking around, as it may be eager. We settled in our rooms spruced up and before long got out to discover a frog utilizing our electric lamps. Sachin true to form wouldn't have anything to do with the snakes. Understanding his dread we disregarded him. Fortunately we figured out how to get o

The Best Ways to Deal With New Job Stress

The Best Ways to Deal With New Job Stress Stress Management Job Stress Print How to Deal With the Stress of a New Job By Elizabeth Scott, MS twitter Elizabeth Scott, MS, is a wellness coach specializing in stress management and quality of life, and the author of 8 Keys to Stress Management. Learn about our editorial policy Elizabeth Scott, MS Medically reviewed by Medically reviewed by Carly Snyder, MD on November 12, 2019 facebook twitter linkedin Carly Snyder, MD is a reproductive and perinatal psychiatrist who combines traditional psychiatry with integrative medicine-based treatments.   Learn about our Medical Review Board Carly Snyder, MD on November 12, 2019 FS Productions / Getty Images More in Stress Management Job Stress Workplace Bullying Effects on Health Management Techniques Situational Stress Household Stress Relationship Stress If youve just started a new job, whether its for the first time or the tenth time, youre probably feeling a little (or a lot of!) stress. There are many new tasks to learn and your bosss or co-workers expectations may be high. New jobs present many changes and challenges, and its natural to feel stress over this. There are several things you can do to both relieve stress and combat its effects.?? Tips for Dealing With New Job Stress Here are some effective things you can do to deal with stress at a new job or in any other situation that requires change and adjustment. Find Support If you can, get support from co-workers, from friends or family, or even an online support group. Talking about whats stressing you out and finding resources should help a lot.?? Dont Be Afraid to Ask for Help You may feel like it shows weakness to ask your co-worker or boss questions, but asking for help  lets them know youre working hard to understand how things flow rather than trying to do something you arent sure of on your own (and potentially messing it up). A side benefit of asking questions is that you can start building a rapport with your boss and/or co-workers. Accept That Theres a Learning Curve Every job is tougher at the beginning as you figure out whats expected of you and how to best perform your tasks. Like everything in life that we do repeatedly, it will get easier and before you know it, youll have found a routine and rhythm and youll feel confident in your job and your ability to do it. Keep this in mind when you start to feel stressed or overwhelmed. Use Quick Stress Relievers Have some quick stress relievers that you can use when youre feeling overwhelmed.?? Breathing exercises, for example, can help slow or reverse the fight-or-flight response you experience when stressed, which saves the wear and tear on your health that chronic stress can cause. Taking a walk can also help calm you down, or  you can keep a stress ball or a fidget spinner at your desk to channel any extra energy and nervousness you might have. Have a Regular Hobby That Helps Relieve Stress Try to maintain some time in your life to do some stress-relieving  activities, so that you feel less stress overall. Ideas include regular exercise, yoga, and engaging in a hobby or another activity that you enjoy, such as drawing, painting, writing, woodcarving, playing an instrument, talking to a friend, listening to music, meditation, gardening, bowling, or fishing. The options are endless! Take Care of Yourself If youre able to eat right, get enough sleep, and take daily vitamins, youll be less worn down physically so youll be less reactive to stress, and youll be in better overall health too.?? Taking care of yourself also boosts your cognitive abilities so you can concentrate and focus better at work.

The Best Ways to Deal With New Job Stress

The Best Ways to Deal With New Job Stress Stress Management Job Stress Print How to Deal With the Stress of a New Job By Elizabeth Scott, MS twitter Elizabeth Scott, MS, is a wellness coach specializing in stress management and quality of life, and the author of 8 Keys to Stress Management. Learn about our editorial policy Elizabeth Scott, MS Medically reviewed by Medically reviewed by Carly Snyder, MD on November 12, 2019 facebook twitter linkedin Carly Snyder, MD is a reproductive and perinatal psychiatrist who combines traditional psychiatry with integrative medicine-based treatments.   Learn about our Medical Review Board Carly Snyder, MD on November 12, 2019 FS Productions / Getty Images More in Stress Management Job Stress Workplace Bullying Effects on Health Management Techniques Situational Stress Household Stress Relationship Stress If youve just started a new job, whether its for the first time or the tenth time, youre probably feeling a little (or a lot of!) stress. There are many new tasks to learn and your bosss or co-workers expectations may be high. New jobs present many changes and challenges, and its natural to feel stress over this. There are several things you can do to both relieve stress and combat its effects.?? Tips for Dealing With New Job Stress Here are some effective things you can do to deal with stress at a new job or in any other situation that requires change and adjustment. Find Support If you can, get support from co-workers, from friends or family, or even an online support group. Talking about whats stressing you out and finding resources should help a lot.?? Dont Be Afraid to Ask for Help You may feel like it shows weakness to ask your co-worker or boss questions, but asking for help  lets them know youre working hard to understand how things flow rather than trying to do something you arent sure of on your own (and potentially messing it up). A side benefit of asking questions is that you can start building a rapport with your boss and/or co-workers. Accept That Theres a Learning Curve Every job is tougher at the beginning as you figure out whats expected of you and how to best perform your tasks. Like everything in life that we do repeatedly, it will get easier and before you know it, youll have found a routine and rhythm and youll feel confident in your job and your ability to do it. Keep this in mind when you start to feel stressed or overwhelmed. Use Quick Stress Relievers Have some quick stress relievers that you can use when youre feeling overwhelmed.?? Breathing exercises, for example, can help slow or reverse the fight-or-flight response you experience when stressed, which saves the wear and tear on your health that chronic stress can cause. Taking a walk can also help calm you down, or  you can keep a stress ball or a fidget spinner at your desk to channel any extra energy and nervousness you might have. Have a Regular Hobby That Helps Relieve Stress Try to maintain some time in your life to do some stress-relieving  activities, so that you feel less stress overall. Ideas include regular exercise, yoga, and engaging in a hobby or another activity that you enjoy, such as drawing, painting, writing, woodcarving, playing an instrument, talking to a friend, listening to music, meditation, gardening, bowling, or fishing. The options are endless! Take Care of Yourself If youre able to eat right, get enough sleep, and take daily vitamins, youll be less worn down physically so youll be less reactive to stress, and youll be in better overall health too.?? Taking care of yourself also boosts your cognitive abilities so you can concentrate and focus better at work.

Hypertension High Blood Pressure - 1938 Words

HYPERTENSION Summer 2015 Bhavneet K. Singh High blood pressure Definition: The heart is supplies the organs and tissues of the body with blood and nutrients it carries. It pumps blood into the blood vessels of the circulatory system. The blood that is pumped into these vessels puts pressure on the walls of the vessels. When the heart muscle contracts during each beat, the pressure rises as well. Blood pressure may be different at different times of the day. It is usually higher when someone first wakes up, after exercise, or when under stress. Having higher blood pressure for short amounts of time is normal, but when blood pressure stays high for most of the time, it can cause serious health problems. High blood pressure, also called hypertension, is a serious medical condition. It is defined as a chronically increased systemic arterial pressure. It happens when the force of the blood pumping through the arteries is too strong. About 7 million people die each year in the United States from illnesses caused by high blood pressure. Blood pressure is measured in units of â€Å"millimeters of mercury† written mm Hg. When measuring blood pressure, there are two different values. Systolic blood pressure is taken while the heart muscle is contracting and pumping oxygen-rich blood into the blood vessels. Diastolic blood pressure is taken while the muscle is relaxing and refilling with blood. Blood pressure measurements are given in pairs, with the upper (systolic) value firstShow MoreRelatedHypertension And High Blood Pressure1703 Words   |  7 PagesHypertension Hypertension is referred to as high blood pressure. Hypertension is frequently asymptomatic in the early stages, and the initial signs are often vague and nonspecific. They include fatigue, malaise, and sometimes morning headache. Consistently elevated blood pressure under various conditions is the key sign of hypertension. 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Gene Theory - Basic Principle in Biology

Definition: The Gene Theory is one of the basic principles of biology. The main concept of this theory is that traits are passed from parents to offspring through gene transmission. Genes are located on chromosomes and consist of DNA. They are passed from parent to offspring through reproduction.The principles that govern heredity were introduced by a monk named Gregor Mendel in the 1860s. These principles are now called Mendels law of segregation and law of independent assortment.

Globalization and Firms Free Essays

string(62) " the economic reasons for government intervention in markets\." 41. With the help of an example discuss the characteristics of globalization. Globalization refers to a fundamental shift in the world economy in which national economies are no longer relatively self-contained entities. We will write a custom essay sample on Globalization and Firms or any similar topic only for you Order Now Instead, nations are moving toward an interdependent global economic system. Within this new global economy, an American might drive to work in a car designed in Germany that was assembled in Mexico by DaimlerChrysler from components made in the U. S. and Japan that were fabricated from Korean steel and Malaysian rubber. A company does not have to be the size of these multinational giants to facilitate, and benefit from, the globalization of markets. 42. Define globalization and discuss it has changed the business environment? Globalization has created many opportunities for businesses to expand their revenues by selling around the world while at the same time reducing their costs by producing in nations where labor and other inputs are cheap. However, globalization has also produced new threats for companies in the form of increased competition. 41. Compare and contrast a pure democracy and a representative democracy. Which type of democracy is more common today? Why? The pure form of democracy is based on a belief that citizens should be directly involved in decision making. In contrast, in a representative democracy, citizens periodically elect individuals to represent them. The elected individuals form a government and make decisions on behalf of the electorate. Because a pure democracy is impractical in advanced societies with tens or hundreds of millions of people, representative democracies are far more common in today’s world. 2. Explain the differences between common law and civil law systems by the approach of each to contract law. Contracts drafted under a common law framework tend to be very detailed with all contingencies spelled out. In contrast, contracts in a civil law system tend to be much shorter and less specific because many of the issues typically covered in a common law contract are already covered i n civil law. 43. What are state-owned companies? Why do they exist? Why do they usually perform poorly? A state-owned company is a company that is owned by a nation’s government. After World War II, many social democratic governments nationalized private companies that were to be run for the public good rather than private profit. Great Britain, for example, nationalized so many companies that by the end of the 1970s, state-owned monopolies existed in telecommunications, electricity, gas, coal, and several other industries. However, because state-run companies such as the ones that existed in Great Britain are protected from competition by their monopoly position and guaranteed financial support, they become inefficient. 1. Compare and contrast folkways and mores. Folkways are the routine conventions of everyday life. Generally, folkways are actions of little moral significance. Folkways include rituals and symbolic behavior. In contrast, mores are norms that are seen as central to the functioning of a society and to its social life. Mores have much greater significance than folkways. Accordingly, violating mores can bring serious retribution. 42. What is the difference between a caste system and a class system? A caste system is a closed system of stratification in which social position is determined by the family into which a person is born, and change in that position is usually not possible during an individual’s lifetime. The caste system is the most rigid form of social stratification. A caste frequently involves a specific occupation. In contrast, a class system is a less rigid form of social stratification in which social mobility is possible through an individual’s personal achievements and/or luck. 43. Discuss why the stratification of a society is important to business. The stratification of a society is significant if it affects the operation of business organizations. In a country like Great Britain for example, the relative lack of class mobility and the differences between classes has resulted in hostility between middle-class managers and their working-class employees. This hostility and the resulting lack of cooperation can make it more difficult for firms to establish a competitive advantage in the global economy. While the last two decades has seen a eduction in the number of industrial disputes in Britain, there are signs that class consciousness may be reemerging in China. 44. Describe the four dimensions of culture as identified by Geert Hofstede. Geert Hofstede identified four dimensions that he claimed summarized the differences between different cultures. According to Hofstede, the power distance dimension focused on how a society deals with the fact that people are unequal in physical and intellectual capabilities. The second dimension identified by Hofstede, individualism vs. collectivism, focused on the relationship between the individual and his/her fellows. Hofstede’s third dimension, uncertainty avoidance, measured the extent to which different cultures socialize their members into accepting ambiguous situations and tolerating uncertainty. Finally, Hofstede’s fourth dimension, masculinity vs. femininity, examined the relationship between gender and work roles. 41. Compare and contrast import quotas and voluntary export restraints. An import quota is a direct restriction on the quantity of some good that may be imported int o a country. The restriction is normally enforced by issuing import licenses to a group of individuals or firms. In contrast, a voluntary export restraint (VER) is a quota imposed by the exporting country, typically at the request of the importing country’s government. Foreign producers agree to VERs because they fear more damaging punitive tariffs or import quotas might follow if they do not. Both import quotas and VERs benefit domestic producers, but hurt consumers through higher prices. 42. What are the political reasons for governments to intervene in markets? There are a number of political reasons why governments intervene in markets. The most common reason for intervention is to protect jobs and industries. Governments may also intervene to protect national security, to threaten punitive retaliatory actions, to protect consumers or to protect human rights, and to further foreign policy objectives. 43. Discuss the economic reasons for government intervention in markets. You read "Globalization and Firms" in category "Essay examples" The economic reasons for government interaction have undergone a renaissance in recent times as more economists support economic reasons for intervention. The oldest argument for intervention is the infant industry argument. Strategic trade policy is the other main reason given for economic government intervention in markets. 44. What is strategic trade policy? Provide an example. Strategic trade policy suggests that in industries where the existence of substantial scale economies implies that the world will profitably support only a few firms, countries may predominate in the export of certain products simply because they had firms that were able to capture first-mover advantages. Boeing’s dominance in the aerospace industry has been attributed to these types of factors. According to strategic trade policy, a government can help raise national incomes if it can ensure that the firms that gain first-mover advantages in such industries are omestic rather foreign. Further, the theory argues that it might pay governments to intervene in an industry if it helps domestic firms overcome the barriers to entry created by foreign firms that have already reaped first-mover advantages. 45. Explain how trade barriers affect a firm’s strategy. There are four main ways trade barriers affect a firm’s st rategy. First, tariffs raise the cost of exporting, putting the firm at a competitive disadvantage. Second, quotas may limit a firm’s ability to serve a country from outside of that country. Third, to conform to local content regulations, a firm may have to locate more production activities in a given market than it would otherwise. Finally, the threat of antidumping actions limits the firm’s ability to use aggressive pricing to gain market share in a country. 41. What is a greenfield investment? How does it compare to an acquisition? Which form of FDI is a firm more likely to choose? Explain your answer. FDI can take the form of a greenfield investment in a new facility or an acquisition of or a merger with an existing local firm. Research shows that most FDI takes the form of mergers and acquisitions rather than greenfield investments. Mergers and acquisitions are more popular for three reasons. First, mergers and acquisitions are quicker to execute than greenfield investments. Second, foreign firms are acquired because those firms have valuable strategic assets. Third, firms make acquisitions because they believe they can increase the efficiency of the acquired firm by transferring capital, technology, or management skills. 42. Compare and contrast the advantages of foreign direct investment over exporting and licensing. A firm will favor foreign direct investment over exporting as an entry strategy when transportation costs or trade barriers make exporting unattractive. Furthermore, the firm will favor foreign direct investment over licensing (or franchising) when it wishes to maintain control over its technological know-how, or over its operations and business strategy, or when the firm’s capabilities are simply not amenable to licensing, as may often be the case. 43. Discuss the various political ideologies and their impact on foreign direct investment. The radical view writers argue that the multinational enterprise (MNE) is an instrument of imperialist domination. The free market view argues that international production should be distributed among countries according to the theory of comparative advantage. The pragmatic nationalist view is that FDI has both benefits and costs. The radical view has a dogmatic radical stance that is hostile to all inward FDI. The free market view is at the other extreme and based on noninterventionist principle of free market economics. Between these two extremes is an approach called pragmatic nationalism. 4. Describe the situations when licensing is not a good option for a firm. Licensing is not a good option in three situations. First, licensing is hazardous in high-tech industries where protecting firm-specific expertise is very important. Second, licensing is not attractive in global oligopolies where tight control is necessary so that firms have the ability to launch coordinated attacks again st global competitors. Finally, in industries where intense cost pressures require that MNEs maintain tight control over foreign operations, licensing is not the best option. 46. Discuss Michael Porter’s interpretation of value creation and competitive advantage. According to Michael Porter, low cost and differentiation are two basic strategies for creating value and attaining a competitive advantage in an industry. Porter argues that those firms that create superior value will achieve superior profitability. Porter notes that it is not necessary for a firm to have the lowest cost structure or create the most valuable product; rather it is only important that the gap between value and the cost of production be greater than that of competitors. 7. Discuss strategic positioning. How does strategic positioning relate to the efficiency frontier? The efficiency frontier shows all of the different positions that a firm can adopt with regard to adding value to the product and low cost assuming that its internal operations are configured efficiently to support a particular position. It is important that managers decide where a firm should be positioned with re gard to value and cost, configure operations accordingly, and manage them efficiently to ensure the firm is operating on the efficiency frontier. 8. Describe the benefits of global expansion for firms. Global expansion allows firm to capture many opportunities not open to firms that remain focused purely on the domestic market. Firms that operate globally have the opportunity to sell their product in a much larger marketplace. Location economies can be realized through global expansion by dispersing value creation activities to the optimal location in the world. International expansion allows a firm to realize greater cost economies from experience effects. Finally, global expansion provides firms with the opportunity to earn a greater return by leveraging any skills developed in foreign operations and transferring them within the organization. 49. What are the two types of competitive pressures that firms competing in the global marketplace face? How do firms respond to these pressures? Firms that compete in the global marketplace typically face two types of competitive pressure that affect their ability to realize location economies and experience effects, to leverage products and transfer competencies and skills within the enterprise. They face pressures for cost reductions and pressures to be locally responsive. These competitive pressures place conflicting demands on a firm. Responding to pressures for cost reductions requires that a firm try to minimize its unit costs. Responding to pressures to be locally responsive requires that a firm differentiate its product offering and marketing strategy from country to country in an effort to accommodate the diverse demands arising from national differences in consumer tastes and preferences, business practices, distribution channels, competitive conditions, and government policies. 50. What are the four basic strategies that firms use to compete in international markets? Under what conditions is each strategy most appropriate? The four basic strategies that firms use to compete in international markets are the international strategy, the global standardization strategy, the localization strategy, and the transnational strategy. The international strategy is most appropriate when there is low pressure for local responsiveness and low pressure for cost reduction. When there is high pressure for cost reduction, but low pressure for local responsiveness the global standardization strategy makes sense. A localization strategy is appropriate when pressure for local responsiveness is high, but pressure for cost reduction is low. Finally, when pressure for both cost reduction and local responsiveness is high, the transnational strategy is best. 52. What are the three challenges related to strategy and structure that firms must accomplish if they are to achieve superior profitability? Superior enterprise profitability requires that firms fulfill three conditions. First, the different elements of a firm’s organizational architecture must be internally consistent. Second, the organizational architecture of the firm must be consistent with its strategy. Third, the strategy and the structure must not only be consistent with each other, they must also be consistent with the competitive conditions prevailing in the marketplace. 53. Discuss the relationship between a firm’s control systems and a firm’s incentive system. Why is this relationship important? The relationships between a firm’s control systems and incentive systems is a close one. Control systems are the metrics used to measure the performance of subunits and make judgments about how well managers are running those subunits. Incentives are the devices used to reward appropriate managerial behavior. The relationship between these two areas is important because incentives are very closely tied to performance metrics. For example, the incentives of a manager in charge of a national operating subsidiary might be linked to the performance of that company. Specifically, he/she might receive a bonus if her subsidiary exceeds its performance targets. 54. Discuss the location of decision-making in a firm that is following a transnational strategy. Decision-making in a firm pursuing a transnational strategy is complex. The need to realize location and experience curve economies requires some centralized control over global production centers. Yet, the need for local responsiveness requires the decentralization of many operating decisions, particularly those for marketing, to foreign subsidiaries. Decentralization of decision-making is also needed to allow subsidiaries the freedom to develop their own skills and competencies—a requirement that is necessary for the global learning component of the transnational strategy. 55. Discuss the sources of inertia in organizations. Is it easy to make organizational changes? Organizations are difficult to change. Within most organizations are strong inertia forces. These forces come from a number of sources. One source of inertia is the existing distribution of power and influence within an organization. Managers who are not happy with the changes are likely to resist and slow the process. A second source of inertia is the existing culture. Since value systems reflect deeply held beliefs, they can be very hard to change. A third source of inertia derives from senior managers’ preconceptions about the appropriate business model or paradigm. Managers may not recognize the value in a given business model that has been successful in the past. Finally, institutional constraints may act as a source of inertia. In some cases, local content rules or regulations pertaining to layoffs can make it difficult for firms to adopt the most effective strategy and architecture. 45. What are first-mover advantages? Discuss the advantages associated with them. First-mover advantages are the advantages frequently associated with entering a market early. One first-mover advantage is the ability to preempt rivals and capture demand by establishing a strong brand name. A second advantage is the ability to build sales volume in that country and ride down the experience curve ahead of rivals, giving the early entrant a cost advantage over later entrants. A third advantage is the ability of early entrants to create switching costs that tie customers into their products or services. Such switching costs make it difficult for later entrants to win business. 46. Explain the relationship between first-mover disadvantages and pioneering costs. When a firm enters a market prior to other international businesses, it can have first-mover disadvantages. These disadvantages may give rise to pioneering costs, costs that an early entrant has to bear that a later entrant can avoid. Pioneering costs arise when the business syste m in a foreign country is so different from that in a firm’s home market that the enterprise has to devote considerable effort, time, and expense to learning the rules of the game. Pioneering costs also include the costs of promoting and establishing a product offering. Finally, an early entrant may be put at a disadvantage, relative to a later entrant, if regulations change in a way that diminishes the value of the early entrant’s investments. 7. Discuss Bartlett and Ghoshal’s perspective on how firms from developing countries should approach international expansion. Bartlett and Ghoshal suggest that companies based in developing countries should use the entry of foreign multinationals as an opportunity to learn from these competitors by benchmarking their operations and performance against them. They argue that the local company might be able to find ways to differentiate itself from foreign companies by focusing on market niches that the multinational ignores or is unable to serve effectively if it has a standardized global roduct offering. Then, the firm from the developing nation may then be in a position to pursue its own international expansion strategy. 48. Discuss strategic alliances. How successful are they? Why do firms form strategic alliances? The term strategic alliance refers to cooperative agreements between potential or actual competitors. Strategic alliances run the range from formal joint ventures, in which two or more firms have equity stakes, to short-term contractual arrangements, in which two companies agree to cooperate on a particular task. Firms enter into strategic alliances for four main reasons. First, strategic alliances may facilitate entry into a foreign market. Second, strategic alliances allow firms to share the fixed costs of developing new products or processes. Third, strategic alliances allow firms to bring together complementary skills and assets that neither company could develop easily on its own. Fourth, strategic alliances can help firms establish technological standards for an industry. How to cite Globalization and Firms, Essay examples

River Island Clothing Co. Ltd. Essay Essay Example

River Island Clothing Co. Ltd. Essay Paper The concern started in 1948 as a little lock-up store in East London selling wool and ladies dressing. As the concern increased stores were added under the name of â€Å"Lewis Separates† and the focal point became ladies dressing. By 1968 there were some 70 shops in the UK and â€Å"Lewis Separates† introduced into a few of its shops a trade name new construct and name. Innovative in design and format these shops used strong colorss. bold manner imagination and dad music to make â€Å"Chelsea Girl. † the first UK concatenation of manner dress shops. With continuing enlargement. menswear was introduced in 1983 under the â€Å"Concept Man† trade name and from 1988 farther development took the signifier of the development ofa new trade name construct of a themed shop offering manner for work forces and adult females. The new trade name was called â€Å"River Island† and today the merchandise scope includes men’s and women’s vesture and fo otwear. accoutrements and cosmetics. We will write a custom essay sample on River Island Clothing Co. Ltd. Essay specifically for you for only $16.38 $13.9/page Order now We will write a custom essay sample on River Island Clothing Co. Ltd. Essay specifically for you FOR ONLY $16.38 $13.9/page Hire Writer We will write a custom essay sample on River Island Clothing Co. Ltd. Essay specifically for you FOR ONLY $16.38 $13.9/page Hire Writer A dedicated in-house design and sourcing squad creates stylish. fashionable and quality vesture stand foring value for money. targeted at the manner witting 18-35 twelvemonth old market. As at 28 December 2002 River Island had net capital resources of ?85. 5 million and achieved gross revenues of ?377. 6 million for the 52 hebdomads. River Island is a entirely owned subordinate of Lewis Trust Group Ltd. which is the parent of a diversified group engaged in the retailing. belongings. leisure and fiscal services sectors. As at 31 December 2002 Group consolidated net capital resources amounted to ?408 million. Relevant Markets River Island designs and retails men’s and women’s vesture. footwear. accoutrements and cosmetics. The bulk of merchandises are designed in-house and sold chiefly under the River Island trade name. although other River Island owned trade names are used. A little proportion of gross revenues are attributable to thirdparty trade names. River Island has shops in over 180 locations Great Britain and Northern Ireland. 9 stores in the Republic of Ireland and elsewhere in the universe retails through franchise spouses in Kuwait. Saudi Arabia. United Arab Emirates. Bahrain. Malta. Cyprus and Poland. In all districts the mark market is the manner cognizant 18-35 twelvemonth old sector. In add-on to its stores. River Island retails through mail order catalogue and web site. RI/11427 ( updated ) 25/05/2004 1 Within the geographic markets mentioned above. the River Island shop card is available merely in Great Britain and Northern Ireland. In add-on to its shop card. River Island accepts a full scope of payment methods from clients. including hard currency. check. recognition and debit cards. Competition within these markets. Our commentary relates merely to the UK market. Within the retail vesture market there is non merely important competition in footings of the figure and differing nature of retail merchants engaged in the sector ( e. g. big section shops. little independent vesture stores. multipleoutlet vesture retail merchants. specializer footwear retail merchants. etc ) but a significant comprehensiveness of pick of merchandise available to the populace. Unlike some other merchandise sectors ( which participate in shop card issue ) the retail vesture sector is non dominated by a limited figure of retail suppliers and the populace has an extended portfolio of dressing retail merchants with which to put their usage. A big bulk of consumers besides have a broad pick of alternate payment methods and/or beginnings of deferred payment ( e. g. shop cards. recognition cards. personal loans. debit cards linked to borrowing installations ) . We see the proviso of a shop card as offering both an alternate payment method ( where the client has the immediate ability to pay by other agencies ) and an extra payment method ( where the client does non hold the immediate ability to pay by other agencies ) . We try to aline the card to our trade name. and to make benefits for our clients. by offering trueness price reductions and particular offers. For a retail merchant such as River Island. the intent of our shop card is chiefly to supply a convenient method of payment ( whether option or extra ) . Whilst it makes no identifiable difference to us whatever agencies of payment a client chooses. we do hold the ability to pass on with card holders and to offer them benefits which we consider will help trueness. We offer such benefits as: †¢ †¢ †¢ †¢ RI/11427 ( updated ) 25/05/2004 Cardholder one-off price reductions Invitations to particular events Loyalty price reductions and wagess Sale previews 2 †¢ †¢ †¢ Discounts on 3rd party services/products Third party offers Forthcoming new merchandise information. These benefits can be promoted by and large. or more specifically targeted based on purchase behavior demonstrated by card disbursement patterns A shop card programme besides provides the retail merchant with a important channel of communicating with clients. a installation non available through other payment mechanisms. The River Island shop card. whilst it includes an optional recognition installation ( i. e. deferred payment ) in common with all recognition cards. is non intended or promoted as a vehicle for longer term adoption. Neither is the card intended as a agency of recognition for those who find trouble with other beginnings of finance. First. the card is a agency of payment. It may be that users choose to utilize the card because they do non hold another agencies of payment at that minute. However. it does non so follow that they will utilize the card installations since they will non incur involvement if they pay off the balance within up to 54 yearss. We have no fiscal involvement in the card operated for us by GE and we have no influence over our card provider’s statistical recognition hiting standards and mechanism. Nor do we hold any contractual influence over the APR charged. or other footings. We sell manner merchandises. It is our position that our clients base their buying determination on their desire for a specific merchandise. We do non believe that the handiness of recognition is a driver as it might be for furniture or larger family goods. Shop cards are usually tied to a individual trade name proprietor or retail merchant and to that extent shop cards do non straight vie with each other. They do vie with other signifiers of payment. peculiarly mechanisms which include the ability to postpone payment. Any analysis of the benefits/costs associated with shop cards and the competitory place of shop cards in the market place. when compared with other agencies of payment. needs to take history of the entirety of the shop card offering and non merely a individual facet of comparing. Barriers to Entry/Ease of Switch overing Merely one or two retail merchants operate their shop cards in-house. River Island uses the services of GE Capital Bank Ltd. In the context of River Is land sing conveying its shop card operation inhouse ( which could potentially better competition in the 3rd party supplier market ) there are important barriers to entry. including. ( a ) Set up costs for RI/11427 ( updated ) 25/05/2004 3 †¢ †¢ †¢ †¢ †¢ †¢ †¢ ( B ) Ongoing costs †¢ †¢ †¢ †¢ †¢ †¢ †¢ Name Centre operation Computer systems to pull off card histories Hardware costs for the above Development of recognition hiting system Human resources recruitment Training Department Compliance Department Recognition hiting Human resources Occupancy costs for call Centre Higher selling costs covering design/print issue of shop card certification Card fabrication costs Bad debts Fraudulent card applications and use Against these barriers the lone important advantage would be fiscal if we could bring forth more value. However. it has to be borne in head – whether in relation to a self-operated card or an alternate to GE – that we need to offer our clients continuity and we need certainty that our card supplier is able to execute. Store card operation is a really hard concern. GE have demonstrated that they can execute. To day of the month few others have done this in the UK. There is a little figure of 3rd party store-card suppliers in the UK market and of those suppliers GE Capital Bank is reported to hold over 50 % of the market. Because of differing accomplishments involved in the proviso of shop card and recognition card services. suppliers ( e. g. Bankss and finance houses ) of other consumer cards and other signifiers of episode recognition are non in a place to readily offer shop card services for retail merchants. Therefore there is some inelasticity in the supply side of 3 rd party store-card suppliers. In add-on. easiness of exchanging by a retail merchant can be influenced by †¢ †¢ †¢ Exclusivity clauses in an bing contract Lengthy contract periods Existing supplier has developed a information base of cardholder disbursement and borrowing behavior that is non readily movable to a new supplier. Financial and clip costs involved in exchanging. New cards have to be issued to all bing cardholders. showing a possible break hazard. Customer Information The River Island store card can be applied for in individual at any one of our stores or electronically through our Website World Wide Web. Riverisland. com. The application process is that prescribed by our card supplier. The card is promoted on the River Island Website. in our mail-order catalogue with application for the card being made through either method described above. but chiefly through our stores. Customer information about the shop card is provided through †¢ †¢ †¢ †¢ In shop postings A â€Å"please take one† cusp available in our stores During history gap processs when the client is finishing an application signifier with our gross revenues advisor A â€Å"welcome† brochure issued at the clip the shop card is issued to the cardholder. The cusp and brochure in peculiar provide written information in untechnical linguistic communication about the benefits of the shop card in add-on to summarizing cardinal information about the fiscal facets of the card. The full footings and conditions of the card recognition understanding are provided to the client on the contrary of the card application signifier. a transcript of which is handed to the client following its completion. The full footings and conditions are besides repeated when the card and any renewal/replacement of it are despatched to the cardholder. Customers are entitled to take away a clean â€Å"voided† application signifier prior to doing any application and successful appliers are besides offered a â€Å"no quibble† warrant that within 60 yearss of opening their history. they may pay off any outstanding balance. shut their history and non be charged any fees or involvement.

Belonging in as You Like It Essays

Belonging in as You Like It Essays Belonging in as You Like It Essay Belonging in as You Like It Essay Essay Topic: As You Like it Belonging can have positive and negative consequences. To belong is to have a secure relationship with a particular facet of society in which one is accepted by those within. The need to feel such a connection with others can often drive us to extreme situations with a varying array of consequences both positive, such as finding one’s place in society, and negative, such as inhibiting one’s sense of self and limiting individuality. Shakespeare’s play As You Like It explores the concepts of traditional notions of belonging by examining filial, fraternal and romantic bonds, the consequences of belonging geographically, and accepted roles of gender. The title itself gives the play to the audience, before any plot is introduced, with the words â€Å"As You Like It† implying the play belongs to those viewing it. In Shakespeare’s context the play was to be seen as meeting his audiences’ expectations and the comedic nature of the plot attempts to ensure this, with a villain the audience collectively hates and a happy ending to ensure comfort and closure. Filial bonds, or family ties, are cemented biologically from birth and form the most primal sense of belonging to human beings. Among all other institutions, that of the family and our relationships within it shape our identities most profoundly and for the longest time. The negative consequences of ostracism from this fundamental unit comprise the core of the plot in As You Like It. Orlando’s pining of his treatment by brother Oliver uses animalistic imagery to illustrate the breakdown of his own family unit. Orlando suggests that Oliver treats his â€Å"animals on dung-hills† better than himself, implying Oliver cares more for his animals than his own brother. The lexical chain used by Orlando of emptiness and nothingness conveys his feelings of ostracism from his family and foreshadows the ultimate fracturing of fraternal bonds in Oliver’s attempts to end his life. This same sense of alienation is repeated in the Court of the Duke Frederick, in which the parallel plot of Rosalind’s excommunication from her usurped father directly correlates to the despair and estrangement felt by Orlando. In Rosalind we also find the character of Celia, a personification of strong congenial bonds, providing an alternative to filial ties in her position as friend and confidante. Rosalind’s connection to the Court shows that a sense of belonging and affiliation can be forged just as easily with place as it can with human beings. The usurping Duke Frederick parallels the malevolent Oliver, with both fracturing family bonds to forward their respective agendas. The cross-over of the first set of parallel plots occurs during Oliver’s attempted murder of Orlando in a wrestling match, with Rosalind meeting Orlando upon his victory. The gifting of Rosalind of a chain to Orlando signifies the symbolic binding of the two, illustrating that said couple belong together. The Forest of Arden and the confines of the Court are constantly juxtaposed as free and liberating verses constrictive and corrupt. The lexical chain of bonds and belonging used by Duke Senior, â€Å"co-mates brothers,† reinforces the notion that feelings of togetherness and mateship are forged and strengthened in the transgressive free space of Arden. These positive connotations imply that the forest engenders such feelings in juxtaposition to the artificiality and malignance of Court. The Forest itself is an allegory for the Garden of Eden, using biblical allusion to associate a paradisical quality to the Forest. Much like Rosalind and Celia to come, Duke Senior reinterprets the coup-de-tat and exile as a positive consequence in which he may educate himself spiritually and find a deeper connection with nature, â€Å"books in brooks, sermons in stones. All characters who come within gradually recognize the Forest’s illuminating and reformative qualities. The tabula rasa allows characters to develop and recognizably change whilst there, re-evaluating their lives and relationships. The isolation from expectations, and providing of ultimate freedom, allows individuals a blank space with which to get in touch with their sense of self. Forced exile from the world she has been within her entire life becomes a turning point for R osalind. The shedding of the restrictive (at the time) women’s gender role conveys the notion that belonging is a societal phenomenon, shaping the way we act and relate to others. Gender dictates the ways that we can belong to society and that society allows us to belong. In the Ganymede guise, Rosalind embodies the ultimate in individual expression by mastering a role she is biologically and socially ill-equipped to take. As Ganymede, Rosalind is free to socialize with Orlando is ways she would be unable to as a woman in Shakespeare’s world. The disguise itself, and associated homoerotic undertones, invite the audience to question their own perception of gender roles and how their constrictive, suffocating structure forces those within to conform to societal expectations and stereotypes. Celia’s aloof view of the women’s exile correlates to her interpretation of the banishment as an opportunity for freedom; â€Å"now we go, content, onto liberty, and not to banishment. † As You Like It shows that consequences for belonging and indeed not belonging can shift from positive to negative and back again depending on interpretation. Indeed, exile and banishment result from a lack of belonging and are seen as negative, however the characters defy the expectation and develop into better people following such negative events. Thus, it is up to the individual to decide for themselves on their view of the consequences; will they be accepted, or will the individual find liberation and enlightenment, allowing for personal rebirth? James Bowers, Line 5 ENA Julieanne Robinson

How to Make a Red Cabbage pH Indicator

How to Make a Red Cabbage pH Indicator Make your own pH indicator solution! Red cabbage juice contains a natural pH indicator that changes colors according to the acidity of the solution. Red cabbage juice indicators are easy to make, exhibit a wide range of colors, and can be used to make your own pH paper strips. Introduction to the Cabbage pH Indicator Red cabbage contains a pigment molecule called flavin (an anthocyanin). This water-soluble pigment is also found in apple skin, plums, poppies, cornflowers, and grapes. Very acidic solutions will turn anthocyanin a red color. Neutral solutions result in a purplish color. Basic solutions appear in greenish-yellow. Therefore, it is possible to determine the pH of a solution based on the color it turns the anthocyanin pigments in red cabbage juice. The color of the juice changes in response to changes in its hydrogen ion concentration. pH is the -log[H]. Acids will donate hydrogen ions in an aqueous solution and have a low pH (pH 7). Materials You Will Need Red cabbageBlender or knifeBoiling waterFilter paper (coffee filters work well)One large glass beaker or another glass containerSix 250 mL beakers or other small glass containersHousehold ammonia (NH3)Baking soda (sodium bicarbonate, NaHCO3)Washing soda (sodium carbonate, Na2CO3)Lemon juice (citric acid, C6H8O7)Vinegar (acetic acid, CH3COOH)Cream of tartar (Potassium bitartrate, KHC4H4O6)Antacids (calcium carbonate, calcium hydroxide, magnesium hydroxide)Seltzer water (carbonic acid, H2CO3)Muriatic acid or masonrys cleaner (hydrochloric acid, HCl)Lye (potassium hydroxide, KOH or sodium hydroxide, NaOH) Procedure Chop the cabbage into small pieces until you have about 2 cups of chopped cabbage. Place the cabbage in a large beaker or other glass container and add boiling water to cover the cabbage. Allow at least ten minutes for the color to leach out of the cabbage.Alternatively, you can place about 2 cups of cabbage in a blender, cover it with boiling water, and blend it.Filter out the plant material to obtain a red-purple-bluish colored liquid. This liquid is at about pH 7. The exact color you get depends on the pH of the water.Pour about 50 - 100 mL of your red cabbage indicator into each 250 mL beaker.Add various household solutions to your indicator until a color change is obtained. Use separate containers for each household solution - you dont want to mix chemicals that dont go well together! Red Cabbage pH Indicator Colors pH 2 4 6 8 10 12 Color Red Purple Violet Blue Blue-Green Greenish Yellow Tips and Safety This demo uses acids and bases, so please make certain to use safety goggles and gloves, particularly when handling strong acids (HCl) and strong bases (NaOH or KOH).Chemicals used in this demo may be safely washed down the drain with water.A neutralization experiment could be performed using cabbage juice indicator. First, add an acidic solution such as vinegar or lemon juice until a reddish color is obtained. Then add baking soda or antacids to return the pH towards a neutral 7.You can make your own pH paper strips using red cabbage indicator. Take filter paper (or coffee filter) and soak it in a concentrated red cabbage juice solution. After a few hours, remove the paper and allow it to dry (hang it by a clothespin or string). Cut the filter into strips and use them to test the pH of various solutions. To test a sample, place a drop of liquid on the test strip. Dont dip the strip in the liquid or else youll get cabbage juice in it. An example of a basic solution is laundry soap. E xamples of common acids include lemon juice and vinegar.

Psychological Testing and Assessment Paper Essay

Psychological Testing and Assessment Paper - Essay Example Psychological test is one of the recognized measurement tools used in psychology. Cohen, Swerdlik and Sturnam (2013) define psychological test as devices and/or procedures used to measure psychological variables with regard to their effects on human life. Cohen, Swerdlik and Sturnam (2013) alternatively define psychological test process of determining psychology related variables through use of procedures and devices designed to produce a sample of behaviors. Counselors, and marriage as well as family therapists rely on psychological tests to accomplish their treatment goals of dysfunctional elements in their clients. Counselors need psychological tests such as interviews and observations to study behaviors and conducts of their clients. Interviews enable counselor to perform personality, intelligence, attitude, brain and behavioral tests on clients. Marriage and family therapists perform personality tests on related individuals facing difficult time to understand inherent motivators to act as they do. Personality tests enable counselors to weigh trust, confidence, courage, self-esteem, understanding, honesty and transparency between and among clients (Nichols, 2013). Measuring trust is usually important in marriage therapy where couples experience problem due to distrust. A married woman may use observations of behavioral change in the partner to suspect infidelity. If the two have not found time to talk about their challenges, the woma n would continue to express distrust in the marriage and behave in a manner that only escalates instability in the marriage. Marriage and family therapists also measure honesty levels in their clients to determine commitment of related members in their relationships. Honesty here, concerns open and truthful communication among members. Therapists understand dishonest communication have great propensity to lead to unstable relationship within families.

Evaluate a range of employee development methods and barriers to Essay

Evaluate a range of employee development methods and barriers to effective learning within organisations - Essay Example â€Å"Development is a continuous improvement process that occurs at both the organizational and individual level. At the organizational level, leaders must actively manage the overall talent mix. Effective leaders recognize the need to fill key positions with individuals who have a competitive advantage in performing their roles when compared with their peers across the industry.† (Koch 2007) This competitive advantage stems from the organizational efforts to train and develop its individuals in a way so as to add value to their expertise as well to the overall organization. History is filled with examples where companies have placed immense emphasis on its employee development programs. Organizations come up with new and novel ways to train and motivate their employees and build their career for the benefit of both the employee and the organization. The learning based interactive system developed by IBM in the 1980s lead to marked improvement in the work quality of its emplo yee. Although when this system was developed IBM was losing from its competitors and incurring loses, but the company in its difficult time did not let do of its employee development and the new and innovative learning system helped the firm come back in business. The employee development methods form the basis of improving employees’ skill and technical expertise. â€Å"Employee Development methods fall under two general categories: on-the-job and off-the-job methods. The on-the-job methods consist job rotation, assistant-to positions, mentoring, special projects, and committee assignments, while off-the-job methods consist of formal education and outdoor training.† (Medina 2006) Talking of the on-the-job training, the most common method is the job rotation which is the systematic movement of an employee from one position to the other in the same or different departments. This method claims to develop employee understanding of the overall organization by moving the em ployee and making him actually do what is required in each unit of the organization. â€Å"Numerous firms have used job rotation, including American Cyanamid Baker Hughes, Ford and Prudential Insurance,† (Griffin & Moorhead 2011) The proponents of this method argue that this type of development is required by the organization in order to familiarize the employee with all the departments and technologies and methodology that the firm uses. But the opponents argue that it makes the employee jack of all trade and master of none. According to them when employees move from one department to the other, the shorter time span adds to the confusion resulting in errors that decreases the productivity of the employee. Another off shoot of the job rotation is the job enlargement which is also known as the horizontal loading of work. It involves the increasing of number of tasks in the same job as performed by previous employees. The rationale behind the inclusion of increasing number of tasks is to reduce monotony of the worker. But this kind of loading takes a toll on the time required to complete the job thus resulting in a decrease in the efficiency. However firms have gained some advantage such as employee motivation due to

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