Handling devices Essay Example | Topics and Well Written Essays - 250 words

Handling devices - Essay Example I would like to reduce the diameter of the rollers so that more of them can be installed. This would allow even smaller materials to be transported through it. 2. Wheel barrow: A wheel barrow is also used to shift materials. The capacity to place material is smaller than that in the roller conveyor. It requires manual work, though the lifting person does not have to bear the load of material. He/she only has to push the wheel barrow. 3. Cranes: A crane is used to lift very heavy materials. It is specifically used for lifting the materials up. It is used to lift such heavy items as precast slabs on the top of walls. These works can not be done manually. If offers the advantage of lifting very heavy materials in very little time without causing any damage. References: Material Handling Equipment Taxonomy. (1999). Material Handling Equipment. Retrieved from http://www.ise.ncsu.edu/kay/mhetax/TransEq/Conv/index.htm#Wheel conveyor.

The Musical Culture of the Country of Burundi Essay Example for Free

The Musical Culture of the Country of Burundi Essay Every nation has its own culture and traditions which has been practiced by the people for many decades or centuries. Most of the cultural practices of a nation are usually passed down to the next generation. Although they are altered to fit the current generation, some parts of the culture remain intact and do not change; they are the same practices done in the past. The same is true with the cultural practices of Burundi. Amidst the various wars and conflict taking place in the country of Burundi, its culture is still upheld by those living in the rural areas. Their traditions are still largely celebrated and practiced by the people. Through the years, the world has seen Burundi as a place filled with violence and conflict. There are times when the news coming from Burundi only involves violence and improper actions of the rebels against the government and vice versa. In addition, mass killings are known to have affected many regions of the country, therefore lessening the chances for recreational activities, education, and other cultural practices to be upheld. Various refuge camps and displaced people have also been distressed by such conflicts. External Influences to the Burundian Culture Historical accounts of Burundi reveal that the country was colonized by various European nations. King Mwezi IV, the ruling leader during the 19th century, feared that his kingdom will be captured by one of the conflicting tribes in Burundi, the Tutsis. Due the King’s fear, he secured the support of Germany to protect his kingdom, instantly turning Burundi into a German colony. After a few years, the German colonizers passed the responsibility to a new European state: Belgium (Institute for Security Studies [ISS], 2005). Hence, these countries were able to influence and engrave their own norms, traditions, and beliefs on Burundians which were incorporated into the cultural practices of Burundi. Music as a Large Part of the Burundian Culture Burundians are people who enjoy arts and music. Music has been a huge part of their lives which could be observed in various types of traditional gatherings and the songs sung in these gatherings. One of these is family gatherings where â€Å"imvyino† songs are performed. Imviyino songs were known to have short refrain which has a strong beat. Such songs often incorporate spontaneous verses which are sung together with the strong beats of the music. On the other hand, â€Å"imdirimbo† song is a more downcast and serious type of music which is sung by a small group of individuals or a solo singer. â€Å"Kwishongora† is another type of song from the traditional music of Burundi that is sung only by men. It is a rhythmic song which is integrated with trills and shouts. For the females, there is also a certain type of song made for them, and it is called the â€Å"bilito† in which is a sentimental form of music (Stanford, 2007), One of the strongest characteristics of Burundi music is the â€Å"whispered singing. † This is expressed by the performer in a low or soft pitch, for it requires the musical accompaniment to be heard clearly (Stanford, 2007). Burundian Musical Instruments Most of the traditional songs of Burundi are played with specific instruments such as â€Å"inanga,† â€Å"idono,† â€Å"ikihusehama,† and â€Å"ikimbe. † The inanga is an instrument composed of six (6) to eight (8) strings which are stretched out in a wooden concave bowl. The idono is known to be the fiddle which is composed only of a single string. The ikihusehama is a musical instrument which is similar to a clarinet woodwind. Lastly, the ikimbe is the linguaphone version of the Burundians. However, the most important musical instrument used by the Burundians is the drums which is considered as a symbol of status and power (Stanford, 2007). Drums are known to be the most significant instruments in the country of Burundi. In the ancient times, drums were not only seen as a plain instrument but a sacred object which was only used for ceremonial events. The beat is one of the most essential elements of the Burundian drums. Certain drum beats are applied depending on the type of event being held, from funerals to enthronement. The beat of the drums is also the main signal that proclaims the start of the agricultural season as well as the propagation of the Soughum seeds which is an important agricultural amenity for the country (Heavenly Planet, 2008). The drums are not only significant to the events, but they are also deeply connected to nature. This strong relationship of drums and nature is evident in parts of the drum, as their names are related to fertility: â€Å"Icahi: the skin (the skin in which the mother rocks her baby); Amabere: the pegs (the breasts); Urugori: the thong stretching the skin (crown of motherhood); inda: the cylinder (the stomach); umukondo: the foot of the drum (the umbilical cord)† (Heavenly Planet, 2008, n. p. ) Royal Drummers of Burundi The Royal Drummers of Burundi is the most acknowledged performers in Burundi. The group is composed of twenty (20) individuals who perform in the most important Burundian ceremonies. Accordingly, due to the significance of the group, they also perform in various celebrations such as funerals, births, coronations, and christenings within the country. This prestigious drum group is known to also perform in various parts of the world. In addition, the Royal Drummers of Burundi is recognized as one of the most acclaimed percussion groups in the world (Smith, 2009). The group is known to be a multigenerational band; therefore, sons are taught by their fathers the art and the significance of performance and playing drums. Most of the time, different drummers switch places in order for them to have a short rest and create a constant flow of music that only stops during the end of the whole program. In addition to drumming, most of the band members are also dancers. The group performs the dances during the opening of the programs (Smith, 2009). Africatravelling. net (2000) commends the performances of the Royal Drummers of Burundi: â€Å"The Drummers of Burundi had the most captivating presence of all the acts at the festival Every moment, every wail from the players fit into the trance impact of the drummers† (n. p. ). The Royal Drummers of Burundi are known to have specific drums that they use to create a specific sound of the drums. One of the types of drums that they use is the â€Å"Ngoma† drums which are â€Å"hollowed out from the trunk of a particular tree called D’umuvugangoma (Corda Africana)† (Heavenly Planet, 2008, n. p. ). Reflection on the Music of Burundi As I have researched in various internet resources, I found out that the Burundi musical culture is not widely known to the world. There are only few resources available for those who are interested in their traditional music. Most books and articles are about the topics of human rights violations, genocides, and war in Burundi. Thus, this suggests the richness of the Burundian culture is often ignored. With the research that I have done, I realized that a single instrument could be a source of power and status. In addition, such instruments could also be a signifier of various events and elements of nature. Due to the conflicts and hostility in the state of Burundi, the international community does not pay significant attention to the rich cultural aspect of this country. However, with the ensemble of Royal Drummers of Burundi, one can say that the rich culture of this African nation lives despite all atrocities. References Africatravelling. net (2000). Bujumbura-Culture. Retrieved February 11, 2009 from http://www. africatravelling. net/burundi/bujumbura/bujumbura_culture. htm. Heavenly Planet. (2008). â€Å"Music That Inspires. † Retrieved February 11, 2009 from http://www. heavenlyplanet. com/featured/dob. html. Institute for Security Studies. (2005). Political System and History. Retrieved February 11 2009 from http://www. iss. co. za/af/profiles/burundi/politics. html. Smith, S. E. (2009). Who are the Royal Drummers of Burundi?. Wise Geek. Retrieved February 11, 2009 from http://www. wisegeek. com/who-are-the-royal-drummers-of-burundi. htm. Stanford, E. (2007). Culture of Burundi. Countries and Their Cultures. Retrieved February 11, 2009 from http://www. everyculture. com/Bo-Co/Burundi. html.

Depression in Teenagers: A Growing Problem Essay -- Essays Papers

Depression in Teenagers: A Growing Problem Who has not, at some time or another, said, â€Å"I am depressed?† It is a line that slips off the tongue of people all too readily when they are bored or unhappy. But most people, when they say that, do not mean that they are clinically depressed, possibly wanting or needing treatment. Sadness is unpleasant but it is not as bad as depression. When people are sad, they keep their self-respect and they feel better after a good cry or a talk with a friend. When people are depressed, self-respect fades, crying does not help at all, and people who are depressed feel alienated around others because they feel like no one understands what they are going through (Brenton 67). Depression is a serious, life-threatening illness that affects approximately thirty million Americans (Brenton 3). Age, race, religion, or educational background is not a factor. Depression strikes anyone at anytime. However, the biggest rise in depression today is in teenagers. Depression in adults is a sad, lonely, and sometimes tragic experience (Cytryn & McKnew, 17). In teenagers it can be even more devastating. Depression gets in the way of teenager’s daily lives. The years of adolescence are supposed to be the â€Å"best years of their lives† and depression robs them of those years. How can life be fun when problems interfere with social life or schoolwork? Teenagers need to know that they cannot simply ignore their symptoms. They need to get help because without the proper help, depression leads to suicide (Bender 70). There are two sides in the current controversy over depression. Some experts believe that depression is an illness while others believe that teenagers are simply making themselves fee... ...talk to. It always helps to discuss problems with someone else. I believe that if a person knows someone who has two or more of the symptoms of depression they should get that person help, before it is too late. Today’s teenagers are the future of our world. Teenagers that are depressed find everything in life to be more complicated and that is simply no way to live. Works Cited Bender, David L. Suicide: Opposing Viewpoints. 1999. San Diego: Greenhaven Press, 2004. Brenton, Sue. Depression. 1996. Rockport: Element Books, 2000 Cohen-Sandler, Roni, Ph.D. â€Å"Do you need a therapist?† Seventeen Dec. 2004: 95. Cytryn, Leon M.D., and Donald McKnew M.D. Growing Up Sad. 1996. Washington: Norton & Company, 1999. Depression in Teenagers. November 2003. Hearts and Minds Network. 8 November 2004 http://www.heartsandminds.org/self/depression.html>.

Bureaucratic Management Essay

The concept of bureaucracy as a form of organization has become the basis for scholars and practitioners to determine and evaluate other forms of organizations. It is observed that whenever an organization is described, one always says it is either bureaucratic or non-bureaucratic. This paper will identify the characteristics of bureaucratic organizations and determine whether these characteristics are still present among organizations of today. This essay is outlined according to the following structure: The first part introduces the reader to Max Weber and his idea of the bureaucratic organization. The major characteristics of the bureaucracy will be presented and discussed in accordance with the original ideas propounded by Weber himself, either through his own writings or those who have exhaustively studied his works. The second part will be a discussion of why the bureaucratic forms developed, interpreted to mean a discussion of their causes as well as the reasons why the bureaucracy flourished as a model of an organization. The final part is a qualified assessment of whether the bureaucratic model of organizations is still being used by present-day organizations or whether organizations have outgrown it and have found the more effective form. Some examples will be given as to what organizational structures or forms are being used by modern organizations. From these will be determined if organizations are now in the post-bureaucratic period. Bureaucracy as a concept of organization was a contribution to theory attributable to either Karl Marx or Max Weber. However, since much of the writings of Karl Marx are more ideologically focused on the philosophical and social aspects, especially with his concept of revolutionary communism, Max Weber has come to be known as the proponent of the concept of bureaucracy. It is safe to believe at this point though, that Max Weber was highly influenced by the writings of Karl Marx and from whose ideas some his bureaucratic concepts are anchored. This essay will focus on the ideas advanced by Max Weber regarding the bureaucratic organization. The description â€Å"Weberian†, referring to his model of bureaucracy, has become a comfortable term to use in bureaucratic literature. Being the major contributor to social theory with his idea of the bureaucratic organization, Max Weber finds himself in major written works, proving his important place in social and political theory. The reasons for his importance are discussed in the Weber book edited by Sam Whimster entitled The Essential Weber: A Reader.   Some reasons provided are: the concept of the work ethic; the idea of rationality as applied to the capitalist enterprise, the bureaucratic organization, and legal systems; discipline; the legitimacy of power and leadership; a general theory of power based on the Marxist idea of social classes; among others.[1] Having said this, one wonders why Weber’s bureaucracy is considered the â€Å"ideal organization† or the â€Å"ideal-type† organization. What makes it become the model for future organizations? What are the main characteristics of the bureaucratic organization? To know these characteristics will help one understand why his model is considered to be an ideal model. The Main Characteristics of Bureaucratic Management The idea of bureaucracy elicits varied reactions from different people. Some agree with the idea of achieving order through its prescribed system of doing things. Others though condemn it for causing problems like delays, corruption, being too impersonal, etc.   In order to put all these in their proper perspective, a good starting point is to define the concept of bureaucracy. The first and most common word one comes across in literature related to bureaucracy is the word rationality. Quoting Weber, Neil Garston defines bureaucracy in the book Bureaucracy: Three Paradigms by way of the categories of rational legal authority.   Authority in this sense is equated to bureaucracy and involves the following: [2] 1. A continuous organization of official functions bound by rules 2. A specified fear of competence involving spheres of obligations marked by division of labor; incumbent being provided with authority to carry out functions; clearly defined means of compulsion 3. The organization of offices follows the principle of hierarchy 4. The rules which regulate the conduct of an office may be technical rules or norms 5. Administration is completely separated from ownership 6. Complete absence of appropriation of his position by the incumbent 7. Administrative acts, decisions and rules are formulated and recorded in writing. Garston goes on to describe the purely bureaucratic organization as â€Å"being from the technical point of view, capable of attaining the highest degree of efficiency and is in this sense the most rational means of carrying out imperative control of human beings.[3] From above description of bureaucracy, a rational organization for Weber is an organization that is governed by a system of rules and procedures. The rationality in his ideal organization is its capability to be efficient through methods of carrying out control over human beings. The aspects of being stable and reliable make the organization ideal. The rules which are observed with much discipline make the organization less prone to instability because there will be none or very little room for sudden changes which may result in the breakdown of the system. In short, Weber advocates an organization that is governed by rules which are universally and strictly followed by people who are qualified and properly trained. Below is a further explanation of the characteristics of a bureaucratic organization, as presented in the initial part of the essay: 1. A continuous organization of official functions bound by rules The application of rules is for everyone and the rules have to be complied with. Rules are applied irrespective of the position and not the person who occupies the position. 2. A specified sphere of competence involving spheres of obligations marked by division of labor; incumbent being provided with authority to carry out functions; clearly defined means of compulsion. Work is divided among the staff, each one with his own set of responsibilities as well as the means of doing them.   The different position titles reflect the nature of how work is divided among the staff, each position has corresponding obligations and responsibilities. 3. The organization of offices follows the principle of hierarchy The organization is characterized by positions of authority structured in a hierarchy, which means that, according to Weber, each lower office is controlled and supervised by a higher one. And consequently, there are positions that have more power. 4. The rules which regulate the conduct of an office may be technical rules or norms. This means that the organization is staffed by qualified people because only those who pass the standards get hired. The basis of both the selection and promotion of employees is the employees’ technical qualifications. As an example, in the specific area of HR, the Personnel Manual codifies the qualification criteria for the selection and hiring of employees. 5. Administration is completely separated from ownership 6. Complete absence of appropriation of his position by the incumbent Both characteristics refer to the aspect of separating administration from ownership in bureaucratic organizations. The means of administration do not belong to the bureaucrat but are concentrated at the top. Thus the position of the official cannot be sold or inherited and it cannot be appropriated and integrated in his private patrimony.[4] The means of production and  administration referred to include the physical equipment like computers, documents, buildings, etc. 7. Administrative acts, decisions and rules are formulated and recorded in writing.   Weber advocates the recording of rules and all acts of administration through written forms, which he referred to as â€Å"the files†. Weber uses the terms â€Å"rational† and â€Å"bureaucratic† in his model. From this, bureaucracy is sometimes called the bureaucratic rationality theory. An assessment of this idea was made by   Stanley Udy Jr. in the article â€Å"Bureaucracy and Rationality in Weber’s Organization Theory: An Empirical Study. The specifications made by Weber were reformulated as either â€Å"bureaucratic† or â€Å"rational† variables. The study proposed the positive and negative associations between the variables from a comparative analysis of 150 formal organizations in 150 non-industrial societies: â€Å"(a) bureaucratic variables are positively associated; (b) rational variables are positively associated; but (c) rational variables are negatively associated with bureaucratic variables†.[5]   This is interpreted to mean that there are certain characteristics of Weber’s bureaucracy that are considered rational, some are considered bureaucratic but not all of them are both bureaucratic and rational. This is really proof of how much dissected the bureaucratic theory is. How about the effect of bureaucracy to the people within the organization? The bureaucracy, with all its characteristic features, is seen as producing two views of the human outcomes, the positive and the negative views. According to the negative view, the bureaucratic form of organization stifles creativity, fosters dissatisfaction, and demotivates employees while in the positive view, bureaucracy provides the needed guidance and clarifies responsibilities, thereby easing role stress and helping individuals be and feel more effective.[6] The Development of Bureaucratic Forms In the writings of Weber, there were already indications of a bureaucratic organization as early as in the middle ages under the rule of the kings. Kings during that time ruled on traveled around ruling the country on horseback, bringing with them sometimes an army of men who took his orders. We have seen this scene fully documented in movies of ancient times where the king, with just a simple signal, can get his men to follow all his orders, from simple documentation to the complex instructions about going into battle. Weber saw this  as a sign of bureaucracy with his idea of the â€Å"bureau†. From this ancient practice developed the concept of the modern bureaucracy.   Presently though, the bureau as Weber described it is structured in a variety of ways, but the main idea of having staff and having an office still remains. Weber called the ancient practice as the â€Å"bureaucratization of the army†.[7] Weber’s works are dominated by the term â€Å"rationalization†. This seemed to have moved him to write about the bureaucratic model as an ideal type organization. According to him, this concept of rationality can help organizations achieve their objectives. The early theories and models of organizations, which are considered traditional, were highly criticized by Weber, saying they are either irrational or non-rational. Being a sociologist mainly, he believed that the use of religion or even magic in ruling is not effective. The traditional forms were not systematic and there were no rules, leaders only relied on feelings and supernatural explanations or perhaps their charisma. While Max Weber considered history to be a force in motivating him to write about bureaucracy, another author provides another dimension to how bureaucratic forms of  organizations developed. Contentions were made relative to Hegel’s Theory of Bureaucracy.   One is that Hegel’s theory is as comprehensive as Weber’s ideal type of bureaucratic organization in that the paradigm of Weber could fit in a reformulation of Hegel’s model.   A second contention made is that Hegel adapts the Aristotelian category of practical judgment to characterize the bureaucratic activity as subsumption. The Weberian concept of rationality is even helpful in the clarifying the difficulties in Hegel’s political thought. This leads to the third contention that Hegel’s model can contribute to a theory of bureaucracy that is more applicable to modern political and social reality.[8] This whole idea of comparing Hegel and Weber and even using the ideas of Aristotle proves that the bureaucracy is an idea that is not only forced by history but also one that is a natural way of organizations. The scholars and other students of bureaucracy only attempted to improve what has already been an idea and a model in the minds of the thinkers. Thus it can be said that the bureaucracy developed as a result of the need to improve the traditional methods of establishing the structures for organizations. While organizations were not really devoid of structure then, the weaknesses in their models became a motivation to come up with better models. The ideas of the bureaucracy were borne out of the need to make them more efficient by following the structure proposed by Weber. The presence of a system of rules governing administration is believed by Weber to be an important component of being able to run the affairs of the organization very smoothly. This is especially true among formal organizations as they are more applicable to them. Another reason is the need to do away with the subjectivity and personal biases governing human organizations. This means that when there are standardized rules, the  possibility of a lot of personal favors may be avoided. It is considered ideal to have the rules universally applied so that there are no personal biases that may arise. The â€Å"personalization† of the positions sometimes cause complex problems arising out of differences in perceptions and attitudes. The impersonal touch of organization is seen to be beneficial in order that rules may be universally applied more easily. The bureaucracy also developed further as it was seen to be continuously pertinent   .. even in today’s socioeconomic and cultural life. This is the position espoused in the book Max Weber and the New Century. The book advances the position that Weber’s ideas are still preeminent and continue to have lasting vitality within social theory. By applying them to topics of contemporary concern, they are expressed in different cultural forms. Sica calls the study of Weber’s works â€Å"a universe of Weberian analysis†.[9]   

Increasing human population Essay

It can transfer genes across species boundaries; more importantly, across huge taxonomic divides. It can also enable the incorporation of laboratory synthesised nucleic acids for designer purposes. GM foods can be divided into those that contain tissues and nucleic acids from the GM source organism (e. g. tomato puree) and those that contain purified derivatives that may be chemically indistinguishable from the same ingredients isolated from non-GMO`s (e. g. the phospholipid, lecithin and other specified oils and proteins from Soya). Provided these purified ingredients are chemically identical to those from non-GMO sources, they should not alter existing health risks. Unfortunately, complete purity is unachievable. Foods that contain original GMO tissue may contain unexpected components and alien nucleotide sequences. The Questions arise: can alien nucleotide sequences be transferred to the gut micro-organisms or be absorbed by human tissues, perhaps through phagocytosis or the agency of viral transduction?. If they can, what are the risks to human health generated as a consequence?. The Biochemist P32 October 1999 ? 1999 The Biochemical Society The technology will allow us to create in major crop plants materials we formerly had to obtain from other sources – such as industrial feed stocks or medicines. Pepper. G. Crop Sciences Dept University of Illinois Crops that resist drought and disease promise to transform the lives of poor farmers -if only they could afford them Five million Brazilians faced starvation this year. This time it was a drought related to El Nii o that halved grain crops in the northeast of the country, but next year it will be something else. Famine is perennial in Brazil. In September Monsanto, the world’s largest supplier of genetically modified seeds, announced it would invest $550 million in Brazil to build a factory producing its herbicide Roundup. Shortly afterwards the Brazilian government made Monsanto’s Roundup-resistant Soya beans the country’s first legally approved, genetically engineered crop. The Soya beans will boost profits for the big landowners who grow them to feed beef cattle for export. But most rural Brazilians are subsistence farmers who do not grow Soya. No help will trickle down from Monsanto’s beans to the starving millions. The story exemplifies the limited contribution genetically modified crops have made so far to eradicating world hunger. It is not that biotech companies are uninterested in the developing world. Far from it: Brazil and other newly industrialising countries are in fact prime targets, with their growing demand for agricultural products, little opposition to biotechnology, and farmers who have risen above hard graft subsistence, but have not yet become customers of the world’s seed and agrochemicals conglomerates. Crops that thrive despite drought and salty soils could also let farmers expand production into marginal lands. And the nutritional content of staples could be improved. If maize, for example, can be made to produce more of the amino acids it naturally lacks, the 80 million people who live almost exclusively on maize would get more protein. Ganesh Kishore, head of nutrition at Monsanto, says: â€Å"We can make it into a complete balanced meal. † Arber. W. (Article: The Bio industry Association 1999 http://www. bioindustry. org/) Genetically modified crops are no more dangerous to the environment than traditional crops and could boost corn, rice and other food yields by as much as 25 percent in developing countries http://www.freep. com/news/health/qdiet141. htm Foods can also be genetically modified to ensure that they last longer by removing or adding certain genes. This process gives them a greater shelf life and means they are less prone to bruising when in transit. They are also less likely to lose their colour and more importantly, retain more of their nutrients. This ultimately gives consumers a better product and reduces the amount of waste for the producers and retailers. Proteins vital to our diets can be added to foods which don’t ordinarily contain them, which is important for people lacking them. In time, this will also be true of vitamins, minerals and other nutrients. http://www. futuradesign. co. uk/gm/ With respect to the information I have studied herein I conclude that genetic modification of foods is not without some induced risk as totally alien genes are being inserted into organisms from unrelated species. This has been shown to possibly alter the new organism’s `properties` as a food substrate either beneficially or adversely. I believe that GM foods have great potential in providing food for an ever increasing population where more traditional agricultural techniques may struggle to cope or fail. However, efficient regulation of the market is necessary and the proactive techniques which have developed to meet this demand may have played a significant part in public rejectance of GM techniques in some countries. Show preview only The above preview is unformatted text This student written piece of work is one of many that can be found in our GCSE Variation and Inheritance section.

Geographic Information About the Country of Peru

Geographic Information About the Country of Peru Population: 31.77 million (2016 estimate)Capital: LimaBordering Countries: Bolivia, Brazil, Chile, Colombia and EcuadorArea: 496,224 square miles (1,285,216 sq km)Coastline: 1,500 miles (2,414 km)Highest Point: Nevado Huascaran at 22,205 feet (6,768 m)Peru is a country located on the western side of South America between Chile and Ecuador. It also shares borders with Bolivia, Brazil and Colombia and has a coastline along the South Pacific Ocean. Peru is the fifth most populous country in Latin America and it is known for its ancient history, varied topography and multiethnic population. History of Peru Peru has a long history that dates back to the Norte Chico civilization and the Inca Empire. Europeans did not arrive in Peru until 1531 when the Spanish landed on the territory and discovered the Inca civilization. At that time, the Inca Empire was centered in what is present-day Cuzco but it stretched from northern Ecuador to central Chile (U.S. Department of State). In the early 1530s Spains Francisco Pizarro began searching the area for wealth and by 1533 had taken over Cuzco. In 1535 Pizarro founded Lima and in 1542 a viceroyalty was established there that gave the city control over all Spanish colonies in the region.Spanish control of Peru lasted until the early 1800s at which time Jose de San Martin and Simon Bolivar began a push for independence. On July 28, 1821, San Martin declared Peru independent and in 1824 it achieved partial independence. Spain fully recognized Peru as independent in 1879. Following its independence, there were several territorial disputes between Peru and neighboring countries. These conflicts eventually led to the War of the Pacific from 1879 to 1883 as well as several clashes in the early 1900s. In 1929 Peru and Chile drafted an agreement on where the borders would be, however it was not fully implemented until 1999 and there are still disagreements about maritime boundaries.Beginning in the 1960s, social instability led to a period of military rule that lasted from 1968 to 1980. Military rule began to end when General Juan Velasco Alvarado was replaced by General Francisco Morales Bermudez in 1975 due to poor health and problems managing Peru. Bermudez eventually worked at returning Peru to a democracy by allowing a new constitution and elections in May 1980. At that time President Belaunde Terry was re-elected (he was overthrown in 1968).Despite its return to democracy, Peru suffered severe instability in the 1980s due to economic problems. From 1982 to 1983 El Nino caused flooding, drought and destroyed the countrys fishing industry. In addition, two terrorist groups, Sendero Luminoso and the Tupac Amaru Revolutionary Movement, emerged and caused chaos in much of the country. In 1985 Alan Garcia Perez was elected president and economic mismanagement followed, further devastating Perus economy from 1988 to 1990.In 1990 Alberto Fujimori was elected president and he made several large changes in the government throughout the 1990s. Instability continued and in 2000 Fujimori resigned from office after several political scandals. In 2001 Alejandro Toledo took office and put Peru on track to return to democracy. In 2006 Alan Garcia Perez again became Perus president and since then the countrys economy and stability have rebounded. Government of Peru Today Perus government is considered a constitutional republic. It has an executive branch of government that is made up of a chief of state and a head of government (both of which are filled by the president) and a unicameral Congress of the Republic of Peru for its legislative branch. Perus judicial branch consists of the Supreme Court of Justice. Peru is divided into 25 regions for local administration. Economics and Land Use in Peru Since 2006 Perus economy has been on the rebound. It is also known as being varied due to the varied landscape within the country. For example, certain areas are known for fishing, while others feature abundant mineral resources. The main industries in Peru are mining and refining of minerals, steel, metal fabrication, petroleum extraction and refining, natural gas and natural gas liquefaction, fishing, cement, textiles, clothing and food processing. Agriculture is also a major part of Perus economy and the main products are asparagus, coffee, cocoa, cotton, sugarcane, rice, potatoes, corn, plantains, grapes, oranges, pineapples, guava, bananas, apples, lemons, pears, tomatoes, mango, barley, palm oil, marigold, onion, wheat, beans, poultry, beef, dairy products, fish and guinea pigs. Geography and Climate of Peru Peru is located in the western part of South America just below the equator. It has a varied topography that consists of a coastal plain in the west, high rugged mountains in its center (the Andes) and a lowland jungle in the east that leads into the Amazon River basin. The highest point in Peru is Nevado Huascaran at 22,205 feet (6,768 m).The climate of Peru varies based on the landscape but it is mostly tropical in the east, desert in the west and temperate in the Andes. Lima, which is located on the coast, has an average February high temperature of 80˚F (26.5˚C) and an August low of 58˚F (14˚C).​ReferencesCentral Intelligence Agency. (15 June 2011). CIA - The World Factbook - Peru. Retrieved from: https://www.cia.gov/library/publications/the-world-factbook/geos/pe.htmlInfoplease.com. (n.d.). Peru: History, Geography, Government, and Culture- Infoplease.com. Retrieved from: infoplease.com/ipa/A0107883.htmlUnited States Department of State. (30 September 2010). P eru. Retrieved from: state.gov/r/pa/ei/bgn/35762.htmWikipedia.org. (20 June 2011). Peru - Wikipedia, the Free Encyclopedia. Retrieved from: http://en.wikipedia.org/wiki/Peru

Preston Brooks Beat Charles Sumner Over Anti-Slavery Speech

Preston Brooks Beat Charles Sumner Over Anti-Slavery Speech In the mid-1850s, the United States was being torn apart over the issue of slavery. The abolitionist movement was becoming increasingly vocal, and enormous controversy focused on whether new states admitted to the Union would allow slavery. The Kansas-Nebraska Act of 1854 established the idea that residents of states could decide for themselves the issue of slavery, and that led to violent encounters in Kansas beginning in 1855. Key Takeaways: Sumner Caned in Senate Chamber Senator Sumner of Massachusetts, a prominent abolitionist, was physically attacked by a slave state congressman.Preston Brooks of South Carolina caned Sumner, beating him bloody in the U.S. Senate chamber.Sumner was severely injured, and Brooks was hailed as a hero in the South.The violent incident intensified the split in America as it moved toward the Civil War. While blood was being spilled in Kansas, another violent attack shocked the nation, especially as it took place on the floor of the United States Senate. A pro-slavery member of the House of Representatives from South Carolina strolled into the Senate chamber in the U.S. Capitol and beat an anti-slavery senator from Massachusetts with a wooden cane. Senator Sumner's Fiery Speech On May 19, 1856, Senator Charles Sumner of Massachusetts, a prominent voice in the anti-slavery movement, delivered an impassioned speech denouncing the compromises that helped perpetuate slavery and led to the current confrontations in Kansas. Sumner began by denouncing the Missouri Compromise, the Kansas-Nebraska Act, and the concept of popular sovereignty, in which residents of new states could decide whether to make slavery legal. Continuing his speech the next day, Sumner singled out three men in particular: Senator Stephen Douglas of Illinois, a major proponent of the Kansas-Nebraska Act, Senator James Mason of Virginia, and Senator Andrew Pickens Butler of South Carolina. Butler, who had recently been incapacitated by a stroke and was recuperating in South Carolina, was held to particular ridicule by Sumner. Sumner said that Butler had taken as his mistress â€Å"the harlot, slavery.† Sumner also referred to the South as an immoral place for allowing slavery, and he mocked South Carolina. Listening from the back of the Senate chamber, Stephen Douglas reportedly said, â€Å"that damned fool will get himself killed by some other damned fool.† Sumner’s impassioned case for a free Kansas was met with approval by northern newspapers, but many in Washington criticized the bitter and mocking tone of his speech. A Southern Congressman Took Offense One southerner, Preston Brooks, a member of the House of Representatives from South Carolina, was particularly incensed. Not only had the fiery Sumner ridiculed his home state, but Brooks was the nephew of Andrew Butler, one of Sumners targets. In the mind of Brooks, Sumner had violated some code of honor which should be avenged by fighting a duel. But Brooks felt that Sumner, by attacking Butler when he was home recuperating and not present in the Senate, had shown himself not to be a gentleman deserving of the honor of dueling. Brooks thus reasoned that the proper response was for Sumner to be beaten, with a whip or a cane. On the morning of May 21, Preston Brooks arrived at the Capitol, carrying a walking stick. He hoped to attack Sumner, but could not locate him. The following day, May 22, proved fateful. After trying to find Sumner outside the Capitol, Brooks entered the building and walked into the Senate chamber. Sumner sat at his desk, writing letters. Violence on the Floor of the Senate Brooks hesitated before approaching Sumner, as several women were present in the Senate gallery. After the women left, Brooks walked to Sumner’s desk and reportedly said: â€Å"You have libeled my state and slandered my relation, who is aged and absent. And I feel it to be my duty to punish you.† With that, Brooks struck the seated Sumner across the head with his heavy cane. Sumner, who was quite tall, could not get to his feet as his legs were trapped under his Senate desk, which was bolted to the floor. Brooks continued raining blows with the cane upon Sumner, who tried to fend them off with his arms. Sumner finally was able to break the desk free with his thighs and staggered down the aisle of the Senate. Brooks followed him, breaking the cane over Sumner’s head and continuing to strike him with pieces of the cane. The entire attack probably lasted for a full minute, and left Sumner dazed and bleeding. Carried into a Capitol anteroom, Sumner was attended by a doctor, who administered stitches to close wounds on his head. Brooks was soon arrested on a charge of assault. He was  quickly released on bail. Reaction to the Capitol Attack As might be expected, northern newspapers responded to the violent attack on the Senate floor with horror. An editorial reprinted in the New York Times on May 24, 1856,  proposed sending Tommy Hyer to Congress to represent northern interests. Hyer was a celebrity of the day, the champion bare-knuckles boxer. Southern newspapers published editorials lauding Brooks, claiming that the attack was a justified defense of the South and slavery. Supporters sent Brooks new canes, and Brooks claimed that people wanted pieces of the cane he used to beat Sumner as â€Å"holy relics.† The speech Sumner had given, of course, had been about Kansas. And in Kansas, news of the savage beating on the Senate floor arrived by telegraph and inflamed passions even more. It is believed that abolitionist firebrand John Brown and his supporters were inspired by the beating of Sumner to attack pro-slavery settlers. Preston Brooks was expelled from the House of Representatives, and in the criminal courts, he was fined $300 for assault. He returned to South Carolina, where banquets were held in his honor and more canes were presented to him. The voters returned him to Congress but he died suddenly in a Washington hotel in January 1857, less than a year after he attacked Sumner. Charles Sumner took three years to recover from the beating. During that time, his Senate desk sat empty, a symbol of the acrimonious split in the nation. After returning to his Senate duties Sumner continued his anti-slavery activities. In 1860, he delivered another fiery Senate speech, titled â€Å"The Barbarism of Slavery.† He was again criticized and threatened, but no one resorted to a physical attack on him. Sumner continued his work in the Senate. During the Civil War he was an influential supporter of Abraham Lincoln, and he supported Reconstruction policies following the war. He died in 1874. While the attack on Sumner in May 1856 was shocking, much more violence lay ahead. In 1859 John Brown, who had gained a bloody reputation in Kansas, would attack the federal armory at Harper’s Ferry. And of course, the issue of slavery would only be settled by a very costly Civil War.

Top French Romance Films

Top French Romance Films Well, they say French is the language of love, so what better language to watch romantic movies in? Cyrano de Bergerac   A beautiful, touching, and humorous love story. Cyrano loves Roxanne but fears rejection due to his overly-large nose. Roxanne loves Christian, and he, in turn, loves her but does not have the ability to express his love. Cyrano helps Christian by expressing his love to Roxanne via Christian. This is the original film, made in 1950 in black and white. It has been remade a few times, including in the US as  Roxanne, with Steve Martin. Le Retour de Martin Guerre (The Return of Martin Guerre) Gerard Depardieu plays a soldier who returns to his wife after many years and has changed so much (in more than just personality) that his wife and neighbors are not sure its the same person. A beautiful love story as well as an interesting look at medieval France. Remade in the US as  Sommersby, with Jodie Foster and Richard Gere. Les Enfants du Paradis (Children of Paradise) A classic French romantic movie, by Marcel Carne. A mime falls in love with a theater troupe actress but faces a lot of competition for her affections. Shot in black and white in 1946 (while Paris was under German occupation), but set in the 19th century. Its a must see! La Belle et la bà ªte (Beauty and the Beast) Youve probably seen some version of this classic French romance, but the original- in black and white- is by far the best. This beautiful, sensual film by Jean Cocteau is about love, inner beauty, and obsession, and is nothing short of a magical fairy tale. Baisers volà ©s (Stolen Kisses) This sequel to 400 Blows (Les Quatre Cent Coups) couldnt be more different to its predecessor. Antoine loves Christine, who is indifferent until her admirer falls for another women. Christine then realizes (decides?) that she does want him after all, and tries to woo him back. A very sweet movie by Franà §ois Truffaut and Jean-Pierre Là ©aud. Les Roseaux savages (Wild Reeds) Andrà © Tà ©chinà ©s 1994 film, set in 1964, is a beautiful coming-of-age story about four teenagers and their experiences with relationships and the effects of Frances war in Algeria. Beautiful cinematography and a great soundtrack, to boot. This film won 4 Cà ©sar awards. Les Nuits de la pleine lune (Full Moon in Paris) A wonderful romantic comedy and the fourth installment in director Eric Rohmers Comedies and Proverbs series. Louise (played by the talented Pascale Ogier, who tragically died the year the film was released) grows bored with her lover and decides to spice up her (love) life. Humor and tragedy ensue. LAmi de mon amie (Boyfriends and Girlfriends) Another from the Comedies and Proverbs series, this film looks at love and friendship. Which is more important: passion or companionship? Is boyfriend-swapping really such a good idea after all? Find out with this movie. Une Liaison pornographique (An Affair of Love) Dont let the ironic French title put you off; this is a beautiful, erotic love story about two people who meet looking for anonymous sex but end up finding much more. A beautiful and mysterious tale of love. LHistoire dAdà ¨le H (The Story of Adele H) The true story of Victor Hugos daughter and her obsession with a French lieutenant. Not a happy story, but certainly a beautiful and intriguing movie.

Managing Design and Sustainability Innovation Essay

Managing Design and Sustainability Innovation - Essay Example It is true that Design Thinking is more than the article has highlighted but it has tried to capture the fundamentals that entail the concept: Question, Care, Connect and Commit (Berger 2010). I believe that Warren Berger captured these sentiments from real interaction with designers so as to develop a comprehensive and simple approach to Design Thinking. The study spans 10 years with at least 100 designers reviewed. It is however true that Design Thinking is more than meets the eye in the actual world of business. When taking the four fundamentals as stated by Berger, it is easy for it to be inapplicable in a real business scenario. The basic reason for this is that the area looked into was the design industry which varies hugely with other industries e.g. entertainment or manufacturing. The basic idea here is customization of Design Thinking to fit the respective context of its application. One example is the critical aspect of trying to uncover end users’ opinions. In some industries which have less contact with end users it would be hard to track significant information unlike in others for example, the service industry. Design in some way focuses on product creation. This is backed by the fact that in Design Thinking the aim is to ensure that what is to get to the end users is of the expected, if not a higher than expected, value. In this endeavor it is overly clear to deduce that one major force behind Design Thinking is product creation. Apple and P&G have been offered as examples of this scenario meaning that it is true in many recent successful companies. These companies have concentrated in designing products that surpass market expectations thereby creating a level of curiosity that has inevitably made competitors think in the same direction. To these companies huge profits have been in the offing. Tracking designers’ work to get an overview of what Design Thinking is all about is a good approach. This is because it

Regulatory bodies are best placed to secure environmental protection Essay

Regulatory bodies are best placed to secure environmental protection Discuss - Essay Example The compliance assurance features of better regulation include initiating time limits for regulatory decision making, minimising the onus of paperwork by substituting to self-reporting and enhanced overseeing of compliance monitoring activities so that business assigns minimum resources and time to inspection by government authorities. The UK government so as to overhaul its industrial pollution control system has introduced a new Integrated Pollution Control system (IPC) as early as 1990 through the Environmental Protection Act. The Environmental Act 1995 established the Environmental Agency. (Bohne: 435). Further, the UK government had combined the additional policy objective with its regulatory reform with an aim to regain more influence on European Environmental Regulations. In UK, the Hampton Principles was adopted which outline a regulatory system perused in tune with the requirements of the 21st century where risk assessment will be the foundation for all environmental program mes. Further, the UK government has made public a regulatory code of practice to compel both the local and national regulators to adhere the Hampton Principles. In April 2008, the Regulators’ Compliance Code came into force. Further, UK has also adopted a common framework for evaluating administrative burdens namely the Standard Cost Model. Moreover, the Impact Assessment Guidance issued by the UK Better Regulations Executive needs an evaluation of the â€Å"aggregate annual cost of enforcement of the regulatory proposal. Further, UK government is contemplating to introduce a system of regulatory budgets to minimise the aggregate costs of its new regulations’ adherence cost on the economy. (OECD2009:45). 2. What are the main characteristics of the British system of regulation? What processes are involved? What are its strengths and weaknesses? The UK government so as to overhaul its industrial pollution control system has introduced a new Integrated Pollution Control system (IPC) as early as 1990 through the Environmental Protection Act. UK can be said to be the leader of an integrated pollution control system not only in the Europe but in the whole world. Section 7 (4) & (7) was successfully exported to Europe from UK. As per Emmot and Haigh (1996:305), the IPC concept of â€Å"Best Available Techniques Not Entailing Excessive Cost† (BATNEEC) which was employed to evaluate the emission limit values which reappeared in the BAT specification of the IPPC directive. As per farthing et al (2003:75), the holistic IPC doctrine of â€Å"Best Practicable Environment Option† (BPEO), though not overtly emphasised in the IPPC directive, is mirrored in the regulations of the IPPC directive to accomplish a greater level of safeguard for environment as a whole, and not to shift the pollution from one medium to another i.e. air, water and land through the Art. 9(1) and (3) of the IPPC directive. (Bohne2006:435). UK assumed the leadership role in EU industrial pollution control legislation by exporting the IPC system to Europe. As per Bell and McGillivray (2006:770), UK kept the administrative and legislative upheaval for the transposition of the IPPC directive to a bare minimum. (Bohne 2006:435). EIA – Environment Impact Assessment It is a technique to make us to understand the probable environmental impacts of major projects both the existing and in the development stages also. The regulations and

Sound and fury Essay Example | Topics and Well Written Essays - 250 words

Sound and fury - Essay Example Heather’s family members seem to be all deaf; two brothers and parents. Peter, one of Heathers families, is a candid head of the anti-implant deaf society who lives on the Island of Long. His life is twisted upside down by his daughter aspiration to hear. After being overpowered by the daughter’s desires, Peter and Nita put on hold their long-standing position about the implant. They later realize that children that are under implant are frequently conversant and mainstreamed interested in the hearing situation. Heather’s parents become frightened that the implant will make their daughter develop a rejection to the American Sign Language and deaf way of life. The family divergence or disagreement arises after one of Peter’s brothers who do not have hearing impediment, and the wife realized that their newborn infant is also having a hearing problem. They decide to put the child under the implant. The clash gets to an intense peak after the part of the family who does have hearing impediment tries to battle for Heather’s right to join the hearing world while the other part of the family (deaf family members) also battle to keep her deaf individuality. In my opinion, the movie talks about respect for culture. From the movie, there is a battle between two different groups, one group supporting the use of cochlear implant while another group is opposed to the use of the device. It is an indication of how important culture is to different people with different conditions especially the disabled group; respect to culture is essential to every individual. Aronson, Josh, Roger Weisberg, Chris Artinian, Nita Artinian, Heather Artinian, Peter Artinian, Brian Danitz, Ann Collins, Mark Suozzo, Ronald Guttman, and Nora Coblence. Sound and Fury. New York?: Docurama,

Space International Essay Example | Topics and Well Written Essays - 1250 words

Space International - Essay Example Between June 27 and July 5, 2014, Webmasters carried out a usability test on the publicly available Space website in Mexico, at the main usability test lab at Bureau of Labor Statistics (BLS) as well as the Webmasters offices. The sessions at Webmaster’s offices provided the required geographic range to the test crew of Space participants; this similar test procedure was used for all the participants.  Between June 27 and July 5, 2014, Webmasters carried out a usability test on the publicly available Space website in Mexico, at the main usability test lab at Bureau of Labor Statistics (BLS) as well as the Webmasters offices. The sessions at Webmaster’s offices provided the required geographic range to the test crew of Space participants; this similar test procedure was used for all the participants.  The functionality tests were majorly based on task cases obtained from Space’s past knowledge of the website’s main purpose and relevant end-user needs. W ebmasters came up with each activity to assess end-user’s ability to easily maneuver around the interface and be able to understand the kinds of information associated with each major areas of the site content.  Basically, Webmasters conducted the usability test to avail answers to some of the following questions:†¢ How well does the new Space website convey a sense of the type of content that users may expect whenever they explore the new Space’s internet sites? It is always essential to use modern technology by upgrading organization system to meet and satisfy user needs (NORLIN & WINTERS, 2001).  Ã¢â‚¬ ¢ Does the new Space website wide navigation and organization ensure effective and efficient access to the relevant content?†¢ How well do users get to understand the meaning of links, site instructions, and labels?†¢ What groups do end users create whenever clustering functions according to discerned similarity?  

Womens Inclusion in Education Essay Example | Topics and Well Written Essays - 1250 words

Womens Inclusion in Education - Essay Example In many countries, cost of education has been rapidly growing and this substantial and constant rise has discouraged many families to provide quality education to their all children. Consequently, this has led to believe that education can only be given to male children rather than to female children. Additionally, in some countries, religious beliefs also discourage the followers to provide education to their girls. For example, in the religion of Islam, some scholars believe that girls should not be allowed to receive an education. And in order to support their perspective, they contend that allowing girls for receiving education would provide them an opportunity to freely interact with boys which become a major cause of social evil in their society. However, this type of belief has made this world more insecure and unsafe as well. For example, because of this backward thinking and perspective, the world is facing the menace of terrorism and extremism; and the events of 9/11 are th e result of one of such insane manifestations. As a result, it can be extracted that because of this thinking, many innocent people lost their lives in that attack. At the same time, the followers of that thinking are still causing harm to humans and humanity as terror attacks are still taking place in a number of other countries as well. In order to avoid this cost, which is being paid by the whole humanity, it has become highly necessary and unavoidable to work against this belief and promote and encourage woman education.

Space International Essay Example | Topics and Well Written Essays - 1250 words

Space International - Essay Example Between June 27 and July 5, 2014, Webmasters carried out a usability test on the publicly available Space website in Mexico, at the main usability test lab at Bureau of Labor Statistics (BLS) as well as the Webmasters offices. The sessions at Webmaster’s offices provided the required geographic range to the test crew of Space participants; this similar test procedure was used for all the participants.  Between June 27 and July 5, 2014, Webmasters carried out a usability test on the publicly available Space website in Mexico, at the main usability test lab at Bureau of Labor Statistics (BLS) as well as the Webmasters offices. The sessions at Webmaster’s offices provided the required geographic range to the test crew of Space participants; this similar test procedure was used for all the participants.  The functionality tests were majorly based on task cases obtained from Space’s past knowledge of the website’s main purpose and relevant end-user needs. W ebmasters came up with each activity to assess end-user’s ability to easily maneuver around the interface and be able to understand the kinds of information associated with each major areas of the site content.  Basically, Webmasters conducted the usability test to avail answers to some of the following questions:†¢ How well does the new Space website convey a sense of the type of content that users may expect whenever they explore the new Space’s internet sites? It is always essential to use modern technology by upgrading organization system to meet and satisfy user needs (NORLIN & WINTERS, 2001).  Ã¢â‚¬ ¢ Does the new Space website wide navigation and organization ensure effective and efficient access to the relevant content?†¢ How well do users get to understand the meaning of links, site instructions, and labels?†¢ What groups do end users create whenever clustering functions according to discerned similarity?  

Positive impact of workplace diversity in the UAE Essay

Positive impact of workplace diversity in the UAE - Essay Example In enhancing the employment of workplace diversity, organizations manage to enjoy benefits such as: Existence of good communication between employees increases the productivity of an organization. However, good communication between employers and employees is as a result of diversification of practices in the workplace. Workplace diversity means the coming together of staff from different cultures and backgrounds. Diversity is important because of many reasons. It promotes equality among people in questing for opportunities. In supporting equal opportunities, make institutions increase their benefits. â€Å"Sharing work and working in teams from different cultures can help to overcome cultural differences through shared experiences when working within a team† (Al-Jenaibi, 2012). Additionally, it is evident that â€Å"managing diversity is about more than equal employment opportunity and affirmative action† (Green, Kepner, Lopez & Wysocki, 2002). Al-Jenaibi B. (2012). ‘The scope and impact of workplace diversity in the United Arab Emirates – An initial study’, Malaysis Journal of Society and Space. Retrieved October 21, 2014, from http://www.ukm.my/geografia/images/upload/14.Geografia-2012_Badreya%20Al-Jenaibi_EDITED-azlan-nn-1.doc.pdf Green, K., Kepner, K., Lopez, M. & Wysocki, A. (2002). Diversity in the Workplace: Benefits, Challenges, and the Required Managerial Tools. Retrieved October 21, 2014, from

The Handmaidens Tale and 1984 Essay Example for Free

The Handmaidens Tale and 1984 Essay The government has the righteous duties to be a national defense for its citizens, to act as an administration of justice in providing law and order for its peoples, and to provide certain public goods and services to its people; though in these present epochs, the government fails to provide certain necessities to its citizens. The two books written in a similar century, both George Orwell’s 1984, and Margret Atwood’s The Handmaid’s Tale, display how the government can use violence as a means of control on its people. In 1984, the government controls its citizens’ lives through manipulating the language of Oceania; Syme, who is Winston’s colleague at the Ministry of Truth, was a lexicographer who developed the new dictionary of the Oceanic language: Newspeak. Also, similar in type, in Margret Atwood’s The Handmaid’s Tale, the government in Gilead uses policies that regulates and controls its women’s desires for sexual activity; the government acts in such a way, because the government has a procreative agenda in Gilead. To conclude, the government in both these novels uses violence as a means of controlling its citizens. In 1984, and The Handmaid’s Tale, both the citizens of Oceania and Gilead have their language distorted; this is in order for them to be infringed from certain goods and services. This language alteration is most evident when Syme informs Winston (the main protagonist in 1984) that by 2050, no individual will be able to understand their conversation; this meaning that the government of Oceania wants to control its citizens’ thoughts. This context can be understood when Syme is in a low-ceilinged canteen deep underground, and he refers to the beauty of the government’s means of controlling the local vocabulary, saying â€Å"Dont you see that the whole aim of Newspeak is to narrow the range of thought? †¦ Has it ever occurred to you, Winston, that by the year 2050, at the very latest, not a single human being will be alive who could understand such a conversation as we are having now? †¦The whole climate of thought will be different. In fact, there will be no thought, as we understand it now. Orthodoxy means not thinking—not needing to think. Orthodoxy is unconsciousness† (Orwell, pg. 68). This quote elucidates to the Big Brother’s master plan in narrowing the range of thought to the Newspeak; it states that all human beings will not understand the conversation they are having, because the universal lexicon will devalue the purpose of thought. The fact that Syme uses words and phrases such as â€Å"thought will be different,† â€Å"there will be no thought,† and, â€Å"Orthodoxy means not thinking,† implies that the government of Oceania will infringe on the citizen’s right to the freedom of thought. Not only does the government of Oceania control the public through changing the vocabulary, but this happens also in the government of Gilead. This language manipulation is most evident when Offred was walking to the shop, and she noticed the written letters on the shop had been painted out, describing, â€Å"Almost all written words anywhere have been removed, even the shops have had the lettering painted out, when they decided that even the names of the shops were too much for us. Now places are known by their signs alone† (Atwood, pg. 1). This quotation refers to how the written words have been removed out of the language, in order for the government to control its citizens from certain services such as literacy. In this quotation, the words and phrases such as â€Å"all written words anywhere have been removed† â€Å"the lettering†¦ painted out,† and, â€Å"places are known by their signs,† means that the government has narrowed the language so m uch, that the citizens can only understand the important sections of the city, and not have the freedom to explore its vicinities. In this paragraph, it is clear that the government uses the manipulation of the local lexicon, subsequently infringing on the rights of its local citizens. In the other novel, 1984 written by George Orwell, the citizens of Oceania experience another form of control, which is the violation to rights of privacy. In this novel, Winston Smith described the conditions in the public square; mentioning that if an individual showed any miniscule sign of deceitfulness, then the government would arrest the criminal immediately, saying, â€Å"It was terribly dangerous to let your thoughts wander when you were in any public place or within range of a telescreen. The smallest thing could give you away. A nervous tic, an unconscious look of anxiety, a habit of muttering to yourselfanything that carried with it the suggestion of abnormality, of having something to hide. In any case, to wear an improper expression on your face ; was itself a punishable offence. There was even a word for it in Newspeak: facecrime (Orwell, pg. 79). In this quotation, Winston Smith refers to the Big Brother’s legislative policies in which telescreens would be set-up in order to have control over its citizens. From the author using words and phrases such as â€Å"terribly dangerous to let your thoughts wander when you were in any public place or within range of a telescreen,† â€Å"the smallest thing could give you away,† and,† improper expression on your face†¦; was itself a punishable offence,† shows that it is even dangerous to express the slightest sign of abnormality in front of the telescreen. Not only does the government in Oceania violate the right to private and public privacy, but that in the government in Gilead the same occurrence ensues. This governmental violation of the right to private and public privacy, is most evident in the gymnasium, where Offred learned who to whisper almost without making a sound, explaining, â€Å"We learned to whisper almost without sound. In the semi-darkness we could stretch out our arms, when the Aunts werent looking, and touch each others hands across space. We learned to lip-read, our heads flat on the beds, turned sideways, watching each others mouths. In this way we exchanged names, from bed to bed: Alma. Janine. Dolores. Moira. June† (Atwood pg. 4). In this quotation, the handmaids exchange names through lip reading and through whispers. Through the words and phrases such as, â€Å"learned to whisper almost without sound,† â€Å"learned to lip-read,† and, â€Å"In this way we exchanged names,† means that because they had to lip-read and whisper, this shows the reader that the handmaids have no privacy to exchange names. In this paragraph, it is noticeable that the government’s legislation and policy mitigates the right to privacy. Furthurmore, in the same novel, 1984, it can be seen that the government subjugates its people from sexual activity. In the novel, Winston fantasizes about making live with Julia as she travels across the field, saying, â€Å"The girl with dark hair was coming towards them across the field. With what seemed a single movement she tore off her clothes and flung them disdainfully aside. Her body was white and smooth, but it aroused no desire in him, indeed he barely looked at it. What overwhelmed him in that instant was admiration for the gesture with which she had thrown her clothes aside. With its grace and carelessness it seemed to annihilate a whole culture, a whole system of thought, as though Big Brother and the Party and the Thought Police could all be swept into nothingness by a single splendid movement of the arm. That too was a gesture belonging to the ancient time† (Atwood, pg. 0). In this quote, Winston Smith dreams about Julia taking off her clothes as she runs across the field. Through the author using words and phrases such as, â€Å"she tore off her clothes,† â€Å"he barely looked at it,† and, â€Å"Big Brother and the Party and the Though Police,† shows that as Julia takes off her clothes on the field, Winston Smith barely looks at her body due to the Big Brother and the Parties legislation for the elimination of sexual p romiscuity. Not only does the government in Oceania take away the right to sexual activity, but that the government of Gilead also infringes on the right to sexual interest. This governmental infringement can also be seen in the ‘Handmaidens tale’ through Offred who makes it clear that throughout the narrative, she is apart of a collectively owned resource. She describes her tattoo as: â€Å"four digits and an eye, a passport in reverse. It’s supposed to guarantee that I will never be able to fade, finally, into another landscape. I am too important†¦. I am a national resource. † (Atwood 65). This quote said by Offred of her describing her tattoo acts as a symbol of the tattoo itself that the government subjugates its people from sexual activity that they would desire and that women are only used as a resource to repopulate. In conclusion, the two narratives in which were written in a similar century, both George Orwell’s 1984, and Margret Atwood’s The Handmaid’s Tale, clearly use their book as a means of foretelling the future of a society monopolized by corruption from future technology by displaying how their government uses violence as a means of control over its people.

Management of Melanoma Brain Metastases (MBM)

Management of Melanoma Brain Metastases (MBM) Abstract: Melanoma is the third most common cause of brain metastases, after lung and breast cancer. Common clinical manifestations include headache, neurologic deficits, cognitive impairment and seizures. The management of melanoma brain metastases (MBM) can be broadly divided into symptom control and therapeutic strategies. Supportive treatment includes corticosteroids to reduce peritumoral edema, antiepileptics for seizure control and medications to preserve cognitive function. Until recently the therapeutic strategies focused on local treatment including surgery, whole brain radiation therapy (WBRT), and stereotactic radiation (SRS). Historically, systemic therapy has had limited utility. Immunotherapeutic drugs like anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1 (PD1) and agents targeting BRAF- MEK pathway have revolutionized the systemic treatment of MBM. Recent clinical trials with these agents have shown activity against MBM and incre asingly being used in clinical practice. In this article, we will discuss epidemiology, biology of MBM and the role of surgery, WBRT, SRS in this patient population. An overview of the currently available systemic therapeutic agents that includes immunotherapy and targeted tyrosine kinase inhibitors (TKIs) and a practical multidisciplinary management algorithm to guide the practicing oncologist will be outlined. Introduction: Recent advances in the management of advanced melanoma have resulted in improved 5-year survival rates, however, MBM remain a significant cause of morbidity and mortality. Approximately 20% of metastatic melanoma patients have brain metastases at diagnosis.   Overall about 50% of stage IV melanoma patients will develop symptomatic brain metastases (1-3). Cerebral hemispheres are the site of 80% of brain lesions from melanoma followed by the cerebellum (15%) and brainstem (5%)(4).Common clinical manifestations include headache, neurologic deficits, cognitive impairment and seizures. Until recently, patients with MBM had a dismal prognosis with a median overall survival (OS) of 6 months (5). The management of MBM can be broadly divided into supportive management and therapeutic strategies. Supportive treatment includes steroids to reduce peritumoral edema, antiepileptics for seizure control and medications to preserve cognitive function. Traditionally, therapeutic strategies focused on local treatment including surgery, WBRT, and SRS. Historically, systemic therapy has had limited utility in the management of MBM. However, the treatment paradigm has changed considerably with the advent of targeted therapy and immunotherapy. Approximately 50% of advanced melanoma patients harbor a BRAF mutation and a number of targeted agents for this mutation and downstream pathway have shown promise in the management of metastatic melanoma. Immunotherapeutic agents like anti- CTLA-4 and anti- PD-1 have shown clinical efficacy in MBM and now constitute first line treatment options for metastatic melanoma. Biology of brain metastases: Until recently MBM were believed to have the highest mutational discordance compared to the primary site (6).   However, Chen et al. reported molecular profiling that included hot spot mutations, global mRNA expression patterns, quantitative analysis of protein expression and activation by reverse protein array (RPPA) analysis of 16 patients (7). In this study, authors reported complete concordance in mutational profile between intracranial and extracranial sites. Despite these similarities crucial differences in the expression of PI3K/AKT pathway were noted by RPPA. Another study compared the expression of BRAF mutation in different sites of metastases in advanced melanoma and showed greater mutational concordance (16/20 patients) in brain compared to other visceral/subcutaneous metastases (8). These studies provide an initial understanding of the molecular characteristics of MBM. With the advent of immunotherapy, tumor microenvironment and immune infiltration has been a focus of intense research. Brain has been traditionally thought of as an immune privileged organ but recent studies have established the existence of a neuro-immune axis and questioned this belief(9). Our understanding of this unique interplay between the immune system and central nervous system has dramatically evolved over time. Berghoff et al. investigated the expression of PD-1, PD-L1, CD3, CD8, CD45RO, forkhead box protein 3 (FoxP3), CD20, and BRAF V600E by immunohistochemistry in MBM samples (10). Varying degrees of tumor infiltrating lymphocytes (TILs) were reported in this study, 33 out of 43 specimens stained positive for CD3(+) T-lymphocytes, 39 for CD8(+) T-lymphocytes, 32 for CD45RO (+)memory T-lymphocytes, 27 for PD-1(+), 21 for FoxP3(+) T regulatory lymphocytes, and 19 for CD20(+) lymphocytes.   Significant tumoral PD-L1 expression (>5%) was observed in 9 specimens while 22 sam ples stained positive for PD-L1 suggesting role of immunotherapeutic agents in MBM. Prognostic indices Although the median OS of MBM is dismal, approximately 5% patients are long term survivors(2). Hence prognostic factors that predict outcomes and can guide the treatment decisions and enrollment in clinical trials are of value. Several large single center series have examined various primary tumor, brain metastases, and patient characteristics predictive of survival (2, 11, 12). Age, performance status, number of brain metastases, extra-cranial metastases, time from primary tumor diagnosis, presence of neurologic symptoms and elevated LDH are factors that determine survival. (13). Sperduto et al proposed a new disease basedscoring index based on 483 newly diagnosed MBM patients from 8 different centers (14). On multivariate analysis, performance status and number of BMs were prognostic for survival in MBM. The outcomes of ds-GPA MBM varied from GPA class I with survival of 3.4 months to GPA class IV with survival of 13.2 months. These prognostic indices have inherent limitations. All of them were evaluated retrospectively, had only overall survival as the end point, did not include molecular and genetic profile of the primary malignancy, and did not take systemic therapy into consideration (15). A large single institutional experience of 366 patients treated to 1,336 brain metastases has also shed some light on the interplay of important prognostic variables in patients with MBM. In this series, characteristics associated with survival included younger age, lack of extracranial metastases, performance status, and treatment with BRAF inhibitors or immunotherapies. This work specifically highlights the importance of modern out outcomes in patients who are eligible for and receive newer targeted therapies. For example, the 12-month survival estimate for patients treated with BRAF inhibitors was 37% compared to 23% for those patients who did not receive these therapies (p=0.01). Moreover, the 12-month survival e stimate for patients treated with immunotherapies was 47% compared to 22% for those patients who did not receive these therapies (p=0.04). Clearly, further work is needed to define the impact of mutation, targeted drugs and immunotherapy in the current era. Diagnosis: The neurologic symptoms associated with brain metastases include headaches, seizures, cranial nerve deficits to motor or sensory deficits. All melanoma patients with neurologic symptoms worrisome for MBM should undergo a gadolinium enhanced magnetic resonance imaging (MRI) of the brain, if no contraindications exist. Guidelines recommend routine MRI of brain with and without gadolinium contrast for patients with stage IV melanoma due to the high prevalence of asymptomatic brain metastases(16). Computed tomography of brain with and without contrast can be used as an alternate imaging. Management: The options available for management of brain metastases include surgery, WBRT, SRS, systemic therapy and symptom management. The management plan to treat these patients should take into account the overall prognosis, performance status and morbidity associated with the treatment. 5.1 Management of symptoms: Supportive care for patients with brain metastases is typically to control the cerebral edema with steroids. Due to minimalmineralocorticoid effect and long half-life, dexamethasone is the steroid of choice, however, other steroids at an equivalent dose can be used and tapered gradually over a two week period(17). A randomized trial in 1990s compared different doses of dexamethasone ranging from 4 mg/day to 16 mg/day and concluded that 4-8 mg/day would provide same degree of clinical improvement in 1 week (18). Routine use of prophylactic anti-epileptics in patients with brain metastases is not recommended(19). When patients have seizures several anti-epileptics are available including phenytoin, carbamazepine, valproic acid and levetiracetam. Non-enzyme inducing agents like levetiracetam are preferred to avoid interactions with systemic agents. 5.2 Neurosurgical Options: Surgery has traditionally been used for management of solitary brain metastases, or large symptomatic brain lesions. Multiple retrospective studies have reported improved survival with surgery compared to best supportive care(13, 20-22). Younger patients with good performance status, fairly well-controlled extracranial disease, solitary brain metastasis, lesions in accessible locations and of small size generally have better outcomes with surgery (21, 23). Surgery is usually followed by radiation boost to the surgical bed by either WBRT or SRS, with an intention of sterilizing the surrounding tissues and preventing local recurrence. Two randomized trials comparing adjuvant WBRT to surgery alone have shown improvement in outcomes(24, 25). Patchell et al. evaluated the role of WBRT post-resection of a single brain metastasis compared to surgery alone(25). Postoperative WBRT resulted in a significant reduction in local and distant intracranial failure. However, no difference in the over all survival or time duration of functional independence was noted. Similar results were seen in the EORTC 22952-26001 study with decreased 2-year intracranial and resection site recurrence without significant survival benefit. Multiple retrospective reports of post-operative SRS have shown improved patient outcomes however prospective data is awaited (26, 27). Bindal et al. showed benefit of resection in select group with multiple metastases in a retrospective review of 56 patients(28).   In practice, surgery plays an important role in debulking or removal of life-threatening lesions. Surgery also provides immediate relief from intracranial hypertension by eliminating the mass effect, and symptomatic hydrocephalus by reestablishing the flow of cerebrospinal fluid (CSF). 5.3 Whole brain radiation therapy: Melanoma brain metastases lesions are generally considered radio-resistant compared to other histologies (29). Randomized trials with WBRT have reported survival in the range of 2.4 to 4.8 months.(30) The ideal dose and number of fractions, balancing the intracranial control and cognitive decline, has been subject to intense debate.   WBRT fraction sizes of ≠¤ 3 Gy do not lead to significant neuro-cognitive decline. A retrospective study compared higher dose of radiation, 40 Gy in 20 fractions with 30 Gy in 10 fractions(31). The 40 Gy group had overall survival of 5.6 months compared to 3.1 months. However most of these trials were not melanoma specific and included patients with all tumor types. Patients who are symptomatic with change in mentation, headaches and seizures but are deemed unfit for surgery or SRS due to large number of metastases, poor performance and uncontrolled extracranial metastases are generally treated with WBRT(32). 5.4 Stereotactic radiation therapy: Stereotactic radiation has been increasingly used in the management of MBM in the last two decades. SRS in MBM results in local control rates of 50-75% at 1 year(33-35). SRS is generally limited to lesions smaller than 4 cm in diameter (36).   In a retrospective review of 333 patients treated with SRS showed a sustained tumor control rate of 73%(35). The 12-month cumulative incidence of local failure was 14% in another single institution experience of 191 patients treated to 793 MBM.   Number of brain metastases that can be treated with SRS has been intensely investigated. SRS for solitary brain metastasis was compared to surgery plus WBRT in a phase III trial that closed prematurely due to poor accrual. The overall survival, freedom from local recurrence and neurological death rates were similar in both groups(37).   Several studies have evaluated the role of SRS in patients with 1-3 brain metastases (38, 39). Aoyama et al. compared SRS alone with SRS followed by WBRT in patie nts with 1-4 brain metastases(38). No difference in neurocognitive function and survival was observed. SRS-alone arm had increased local and distant intracranial failure. A phase III trial compared WBRT followed by SRS to WBRT alone, in 333 patients with 1-3 brain metastases from different histologies that included only 13 MBM patents (40). Performance status at six months improved significantly with addition of SRS to WBRT. SRS for patients with 5-10 brain lesions was evaluated in a multi-institution prospective observational Japanese study of 1194 patients(41). The overall survival, neuro-cognitive function and post SRS complications did not differ for patients with 5-10 brain lesions compared to 2-4 brain lesions(42). 5.5 Systemic therapy: Traditional systemic therapy had a limited role in MBM due to challenges of drug delivery in the brain from blood brain barrier (BBB) with its tight junctions and efflux pumps (P-gp and MRP transport proteins) (43). The concept of localized disruption of BBB at the site of brain metastases has been proposed, as demonstrated on MRI by contrast enhancement (44). Chemotherapy: Chemotherapy agents have not shown good activity in MBM. Dacarbazine which is the approved chemotherapy for metastatic melanoma does not cross the BBB(45). A number of studies evaluated the role of alkylating agents with good BBB penetration such as temozolomide (TMZ), lomustine and fotemustine in MBM patients. In a phase II trial Agarwala et al. enrolled 151 MBM patients with no local radiation therapy for BM to receive TMZ (46). TMZ use showed a modest intracranial response of 6%, median PFS of 4.3-5.2 weeks and median OS of 3.2 months. Two phase II trials of WBRT with TMZ(47, 48); or thalidomide, WBRT with TMZ (49) failed to improve the response rates significantly. Lomustine in combination with TMZ showed modest efficacy in a phase I/II study(50).   Intracranial activity of fotemustine was first reported in a phase III trial of fotemustine versus dacarbazine for metastatic melanoma (51). This led to a randomized phase III trial that compared fotemustine plus WBRT to fotemustine alone in MBM (52). The response rates were 7.4% for fotemustine alone and 10% for fotemustine plus WBRT. Fotemustine is not currently approved by FDA for use in MBM due to delayed thrombocytopenia and leukopenia(53). Targeted therapy: BRAF, NRAS and KIT are three common, mutually exclusive driver mutations seen in metastatic melanoma (54, 55). Of these three, BRAF mutation is the most common mutation seen in approximately 40-50% of patients with advanced melanoma. The presence of BRAF, NRAS increases the risk of CNS metastases seen in patients with   advanced melanoma. Prior studies have reported 24% CNS metastases rate in BRAF and 23% CNS metastases incidence in NRAS mutant melanoma compared to 12% rate in those who lack these mutations(56). Dabrafenib and vemurafenib target BRAF V600 mutation and FDA approved for metastatic melanoma. A phase I trial of dabrafenib in ten patients with untreated asymptomatic brain metastases, intracranial response was seen in 8 patients (four CR, four PR) (57). This impressive 80% response rate prompted the phase II trial of dabrafenib in BRAF mutant melanoma brain metastases (BREAK-MB) (58). This multicenter open label study accrued 172 patients asymptomatic brain metastases with BRAFV600E or BRAFV600K mutation and one measurable lesion (defined as atleast 1 cm in diameter). Cohort A consisted of 89 patients who were radiation naive and cohort B consisted of 83 patients who had failed prior radiation therapy for BM. BRAFV600E patients had an intracranial response rate (IRR) of 39% (29/74) in cohort A and 31% (20/65) in cohort B, PFS of 16.1 weeks in cohort A and 16.6 weeks in cohort B with OS of 33.1 weeks in cohort A and 31.4 weeks in cohort B. BRAFV600K patients had a lower IRR of 7%(1/15) in cohort A and 22% (4/18) in cohort B. This trial supports the efficacy of dabrafenib in BRAF mutant MBM patients, especially those with BRAFV600E mutations with acceptable toxicity. In an open label study of 24 non-resectable, untreated MBM patients harboring BRAFV600 mutation, treatment with vemurafenib resulted in tumor regression of more than 30% (7/19)and partial response was seen in 3 patients. Median PFS and OS was 3.9 and 5.3 months respectively in this study. In a phase II study, 146 BRAF mutant MBM patients were treated with vemurafenib(59). The first cohort included 90 patients with untreated BM, the second cohort comprised of 56 patients with previously treated BM.   Complete response was noted in 2 patients, with 14 PRs, and a best objective response rate of 18%. In previously untreated MBM, the median intracranial PFS and OS were 3.7 months and 8.9 months respectively. Previously treated MBM had similar PFS and OS of 4.0 months and 9.6 months respectively. There is no prospective data of safety and efficacy of combination of BRAF inhibitors and radiation therapy. Most reports are retrospective in nature with increased incidence of dermatitis seen in extracranial skin associated with concurrent use of BRAF inhibitors and radiation (60). Rompoti et al. reported five patients with MBM treated with combined radiation and BRAF inhibitor(61). Two patients underwent SRS and three received WBRT. Patients treated with SRS did not experience any skin adverse effects while all three patients treated with WBRT noted grade1/2 dermatitis. A retrospective analysis evaluated effectiveness of vemurafenib and radiation in BRAFV600 MBM (62). All of them received vemurafenib, six patients underwent SRS, two received WBRT, one received SRS and WBRT and three underwent surgery and radiation. Thirty-six of the 48 index lesions responded with 23 (48%) CRs and 13(27%) PRs. Major limitations were the retrospective nature of the study, small number, and pretreat ed patients with radiation and systemic therapy including ipilimumab. Several small retrospective case series have reported outcomes of MBM treated with targeted agents and SRS/WBRT (Table-1). A recent study of 19 patients with BRAF mutations undergoing SRS and concurrent BRAF directed therapies has shown impressively few local failures (12-month cumulative incidence of 1%). Additional studies of combination therapy are clearly warranted. Immunotherapy: Melanoma is an immunogenic malignancy (63) with a high mutational burden that results in high number of neo-antigen(64). It has been proposed that the relatively high neo-antigen burden makes this malignancy more susceptible to immunotherapy. However, the brain has traditionally been considered an immunologically privileged site due to the presence of the BBB. Recent studies on the intracranial tumor microenvironment as elucidated above have suggested otherwise, showing CD8 T-cells, CD 20+ cells, T-regulator cells and PD-L1 expression within intracranial tumor(10). The intracranial activity of interleukin-2 (IL-2, one of the first immune modulatory agents) was reported in two retrospective reviews(65, 66).   A response rate of 5.6% was seen in 37 patients with untreated brain metastases within a larger group of 1069 metastatic melanoma and renal cell carcinoma patients treated with high dose IL-2(65). In a second report, two of the 15 brain metastases patients treated with high dose IL-2 showed CR (66). No prospective trials were initiated with high dose IL-2 due to concerns for cerebral edema and neurotoxicity. Two pathways that have revolutionized the management of advanced melanoma are those involving CTLA-4 and PD-1/PD-L1.   The CTLA-4 receptor is expressed exclusively on T-cells and downregulates the interaction between antigen presenting cells and T-cells. Ipilimumab is a fully human monoclonal antibody against the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)(67). The pivotal phase III trial that compared ipilimumab with or without gp 100 peptide vaccine to gp 100 vaccine as a single agent allowed enrollment of patients with asymptomatic and/or previously treated MBM (68). A non-significant trend towards better survival in the MBM subgroup was noted among the patients treated with either ipilimumab alone or ipilimumab plus gp 100 compared to gp 100 alone(69). In an expanded access program (EAP) in Italy, 146 MBM patients received ipilimumab and a global response rate of 12% was seen (70). An American EAP reported a 1-year overall survival rate of 20% among 165 MBM patients tr eated with ipilimumab (71). Margolin et al. conducted an open label phase II clinical trial of ipilimumab for MBM (72). The trial enrolled 72 patients 51 patients in cohort A (those who were not on steroids for cerebral edema) and cohort B of 21 patients (on treatment with steroids). According to the WHO criteria, the response rate was 18% (9/51) in cohort A compared to 5% (1/21) in cohort B, and by immune-related response criteria the response rate was 25% (12/51) in cohort A and 10% (2/21) in cohort B. The median OS was 7.0 months and 3.7 months in cohort A and cohort B respectively. The study concluded that ipilimumab can be used safely in MBM patients. An Italian phase II trial tested a combination of ipilimumab and fotemustine in patients with advanced melanoma including asymptomatic MBM patients (73). A total of 20 patients (out of 83 patients) had asymptomatic MBM, and among these patients the study reported a PFS of 3.0 months and 3-year OS rate of 27.8% (74). A randomized, 3 arm, phase III trial of fotemustine, versus fotemustine plus ipilimumab, versus ipilimumab plus nivolumab (NIBIT-M2) is currently recruiting patients (75). Several retrospective studies have evaluated the safety of combining ipilimumab and radiation therapy (SRS or WBRT), and prospective trial data is forthcoming (76-78). PD-1 receptors are expressed on several cells including T-cells and antigen presenting cells. Their interaction with PD-L1 ligands on tumor cells leads to T-cell exhaustion and downregulation of tumor-specific immune response(79). Nivolumab and pembrolizumab are two anti-PD-1 antibodies that are currently approved for the management of advanced melanoma, and several others are under evaluation. An open label, single-center, phase II clinical trial is currently enrolling patients with untreated brain metastases from melanoma or non-small cell lung cancer (80). In a published early analysis, a response rate of 22% (4 patients) was reported in a total of 18 MBM patients and the responses were durable. Authors noted a high concordance between systemic and brain metastasis responses. Additionally, 11% (2 patients) had stable disease. Intriguingly all responders lacked a BRAF mutation. Relatedly, 4 patients were not evaluable either due to rapid progression necessitating BRAF-targeted ther apy (3 patients), or intralesional hemorrhage (1 patient). Toxicities in the MBM cohort included grade 3 transaminitis (1 patient), as well as grade 1-2 seizures (3 patients) and grade 3 cognitive dysfunction (1 patient) from peritumoral edema. Leptomeningeal disease in melanoma   Leptomeningeal disease (LMD) is a subset of metastatic with extraordinarily poor prognosis and median survival of 8 weeks(81, 82). About 5% of malignant LMD originates from melanoma (Kesari) and up to 23% of melanoma cases develop LMD(1, 83). Primary leptomeningeal melanoma also exists as a separate clinical entity and should be a consideration in the context of a person with multiple congenital melanocytic nevi(84). Diagnosis of LMD is usually made based on the combination of neurologic symptoms along with corresponding leptomeningeal enhancement on MRI. While cytology from cerebrospinal fluid (CSF) is considered to be the gold standard for LMD diagnosis, sensitivity of this testing ranges from 50% to 80%, depending on number of lumbar punctures performed (85). Like with MBM, treatment of LMD with chemotherapy has low response rates(86). The clinical course of LMD is more treacherous in melanoma in other malignancies given the propensity for melanoma LMD to hemorrhage(87). Molec ular characterization of melanoma LMD suggests a higher percentage of BRAF mutations in comparison to the general melanoma population (68% v 45%), based on a single center melanoma LMD cohort of 60 patients(76). Several case reports have been published highlighting complete and partial responses as well as prolonged ongoing survival beyond 15-18 months with BRAF inhibitors (86). Immunotherapy approaches, including intrathecal IL-2, adoptive cell therapies with tumor infiltrating lymphocytes (TILs) and cytotoxic T-lymphocytes (CTLs), and immune checkpoint inhibitors, have also reported prolonged survival in comparison to historic medians (86). A single center study of 38 patients with melanoma LMD who were treated with intrathecal IL-2 reported a median survival of 9.1 months, and the best 15% of patients reached a median survival over 24 months(88). Ongoing survival over 18 months in a melanoma LMD case was reported with WBRT followed by ipilimumab, an immune checkpoint CTLA-4 inhib itor; in this case, treatment with ipililumab resulted in complete radiologic response(89). A phase II trial of combination immunotherapy with ipilimumab and nivolumab, a PD-1 inhibitor, in melanoma LMD has recently opened to accrual(90). In summary, these early data suggest that both targeted therapy and immunotherapy have efficacy in melanoma LMD and can result in durable responses well over a year. Upcoming trials addressing melanoma LMD with newer therapies will likely yield significantly improved survival data over the next decade. Conclusion: Despite significant recent improvement in the outcomes of patients with melanoma, brain metastases remain a major determinant of mortality and morbidity in melanoma patients, and patients with MBM remain in the worst prognostic category. The vast majority of clinical trials with newer agents exclude patients with MBM, thus data on the effectiveness of new drugs in the context of MBM is still lacking. Understanding the biology of MBM and its clinical response to newer agent and particularly combinations of agents and strategies is crucial to increasing the longevity of the poorest-risk melanoma. Appropriate care of MBM begins with diagnosis. In melanoma, the brain is a common site of metastatic spread, both early and late. It is crucial to begin screening patients for MBM at diagnosis, and NCCN guidelines have recently been updated to reflect this changing diagnostic paradigm. The frequency at which to repeat imaging is still not known. Several therapeutic options now exist for the treatment of MBM (A proposed algorithm is provided in Figure-1). Surgical resection, radiation therapy, targeted therapy and immunotherapy all show some degree of efficacy with MBM.   Even in cases of LMD, perhaps the worst subset of MBM in terms of survival, treatment with targeted therapy and immunotherapy can induce prolonged survivals from historic means. Initial reports involving combinations of these therapies, such as radiotherapy with either targeted therapy or immunotherapy, appear promising, but will need to be systematically studied in cohorts with larger numbers. Equally important will be the parallel investigation of predictive markers in MBM with these therapies and combinations. Thus, whenever possible, patients with a new diagnosis of brain metastases should be enrolled in appropriate clinical trials. If an appropriate clinical trial is unavailable, treatment decisions should be made with input from a multidisciplinary t eam including radiation oncologists, neurosurgeons, and medical oncologists.