India Today Essay

Slowly, but surely, in the year 2000, India is beginning to erase the Nehruvian social contract that created the public sector and bound the employees to a corporate unit and the corporate unit to the nation. In the age of restructuring and re-engineering that this has ushered, employees are no longer valued resources but expendable commodities. And likewise, the employers are no longer demi-gods and fuedal lords in one. They are going to become one with a mind-boggling scenario of a private sector, where the growing manager with the corporate experience of a lifetime might suddenly be written off as hopelessly old fashioned; and replaced with a young nerd, who along with, maybe the new owner’s driver, will be sitting on a stack of stock-options valued in millions. Clearly it is time to think seriously about wealth and what it means to be wealthy in India today. The last time Indians thought self-cautiously about being rich through joint holdings with non blacks, was in the 19th Century when the East India Company revealed to the worldly wise Indians occupying crucial positions within the system, the plunder-potential of their land. They got busy right away. This continued for almost a century till historic events triggered off a freedom struggle under Gandhi over the equitable distribution and domestication of India’s wealth. The idealism lasted barely two decades. Political debates then were all about the baneful influence of capitalism and money. It was okay to generate jobs but not great wealth which could corrupt our most sacred institutions. Slowly some crusading investigative journalists and economists followed this logic and began to glean disturbing facts about the trumpeters of this brand of Hindu socialism. They made dark revelations repeatedly about questionable personal behaviour and financial chicanery that they had discovered among various political groups in power.

Looking At The Advanced Technology Of Construction Construction Essay

The demand on application of advanced engineering in building industry necessitates uninterrupted employment of new engineering work force and geting of latest machinery. A building house would necessitate a immense investing in order to last in acquiring new occupations. Therefore, really frequently, a building undertaking is managed by a general contractor, which sublet the plants out to different subcontractors so that the general contractor can salvage on building cost to vie in monetary value [ 1 ] Subcontractors are specialist in the executing of a specific occupation, they act as a agents of the production system of the contractor company in providing stuffs, work force, equipment, tools or designs [ 2 ] . Chiang [ 1 ] concludes that farm outing is indispensable to salvage building cost of general contractors to vie on monetary value. Teixeira & A ; Couto [ 3 ] besides agreed that increasing of specialization thorugh subcontracting can help in achieving the undertaking objectives. When the range of work and logical dependences between subcontractor plants are non to the full understand by general contractor and proprietors, it became a critical job to the success of complex and fast-paced undertakings. Cost judicial proceeding and disgruntled clients due to the struggle between general contractor, subcontractors and other undertaking participants would so followed [ 4 ]SubcontractorSubcontractor is a common term used in building. Due to the singularity of each building undertaking, the work force is transeunt, multiple trade are involved, each undertakings are planned and worked in short clip frames, and assortment of stuffs and equipments required, one individual building undertaking is frequently sublet to many subcontractors [ 2 ] , [ 5-12 ] . Subcontractors can lend more than 50 % [ 13 ] , and can be every bit much as 90 % of entire undertaking value to a building procedure [ 5 ] . A building undertaking is awarded to a general contractor or premier contractor or chief contractor or chief contractor, which resorts their work out to specialise outside house to transport out specific undertaking activities. General contractors are responsible for pull offing the undertaking such as contract disposal with clients, undertaking funding, stuff and equipment procuring, and supervising the undertaking advancement [ 14 ] . Harmonizing to Albino & A ; Garavelli [ 13 ] , the general contractor ‘s perfomance are strongly dependent on subcontractors. This statement is reinforced by Mbachu [ 15 ] which stated that the ability of the general contractor and adviser to present the undertaking within clip, quality and cost depends mostly on public presentation of subcontractors. A subcontractor is a building house that contracts with a general contractor to execute some facet of the general contractor ‘s work. In most building undertakings, a critical function is played by subcontractors who are hired to execute specific undertakings on a undertaking. In the usual instance, the general contractor will execute the basic operations and farm out the balance to assorted forte contractors. Subcontracting is used much more extensively on lodging and edifice building undertakings than on technology and industrial undertakings [ 16 ] .Types of SubcontractorsAttempts have been meade to distinguish subcontractors. In Hong Kong, Ng et Al. [ 6 ] classified subcontractors to ( i ) equipment-intensive subcontractors ( who are hired due to their specialized works and equipments ) , and ( two ) labour-intensive subcontractors ( those who are hired as a consequence of their specialized labour resources. Costantino et Al. [ 17 ] revealed that labour-only subcontractor beneficial the subcontractor by cut downing the cost of mobilisation and buying stuff. Furthermore, it besides offers economic advantages to the general contractor by avoiding the mark-up of full subcontracting. Quality jobs and claims may still happen in acquiring the supply of stuff for application of this labour-only subcontractor. Therefore, some general contractors prefer full subcontracting to switch hazard and liability. Partnering relationship between general contractor and subcontractors were proposed to make a win-win state of affairs [ 5 ] , [ 18 ] . Harmonizing to Lee et Al. [ 18 ] , this long-run relationship must be established to avoid adversarial relationship between general contractor and subcontractor. Several types of relationships between general contractor and subcontractor are discussed, competitory relationships and strategic relationships were among them. Comparison theoretical account based on dealing cost for both general contractor and subcontractor are developed severally for each relationship.Multilayer SubcontractingFurther subcontracting by subcontractor, or called multilayer subcontracting/latent subcontractor, let the subcontractor to be less vulnerable to fluctuation in concern, have more flexibleness in work force coordination, and be able to cut down cost of direction [ 7 ] . In Turkish, pattern of farm outing work by subcontractors to secondary subcontractor is widespread [ 19 ] . A survey on 35 general contractors and 56 subcontractor organisations revealed that most of them are willing to sublease their work under overload of work or clip force per unit area. When â€Å" latent † subcontractor happened, the extent of subcontracting is even larger. â€Å" Latent † subcontracting, or multilayer subcontracting is the farther farm outing down the watercourse by subcontractors with or without the cognition or consent of the general contractor or client. This has been alleged to be one of the major causes of hapless building quality and building site safety in Hong Kong [ 1 ] , [ 7 ] . Ekstrom et Al. [ 20 ] argues that payment to the 2nd grade subcontractor/suppliers can be portion of the public presentation measuring when measuring subcontractor.Problems of SubcontractingAbility to pass on and organize the work of subcontractors has been identified as one of the chief conceptual determiners of building undertaking direction competency in China [ 21 ] . Subcontractor failure has been listed as one of the hazard allocated to general contractor in building contracts [ 22 ] . This is supported by El-Sayegh [ 23 ] which stated that subcontracting is hazardous and can take to low quality, delayed completion and insecure pattern. Another hazard created by subcontractor is the possibility of them to transgress contract and difference with the general contractor. Hence, subcontracting has been listed as one of the important factors doing hold United Arab Emirates [ 24 ] , [ 25 ] and Malaysia [ 26 ] , [ 27 ] .PERTINENT STUDIES ON SUBCONTRACTORFocus of research workers goes to either finding the components of farm outing or developing new approaches/techniques to choose and/or manage subcontractors. Subcontractor has become an issue on its ain, separated from selection/management of general contractor by client/consultants due to its complexness. Numerous subcontractor choice and monitoring theoretical account has been proposed [ 4 ] , [ 13 ] , [ 28-30 ] .Choice of SubcontractorMany choice methods of subcontractors has been proposed in the literature. Arslan et Al. [ 28 ] developed a web-based subcontractor rating system ( WEBSES ) to ease the choice of subcontractors. The standards for measuring was identified by calculators of building house in USA based on a database of about 4000 subcontractor houses. Ng & A ; Luu [ 31 ] developed a theoretical account for subcontractor enrollment determination through case-based logical thinking attack. 12 experts were interviewed to supply indispensable stairss needed for distinguishing good and bad subcontractors. The theoretical account developed use each properties ‘ calculated evaluations for designation of fiting instances and similarity mark of each single instances. The historical information of subcontrators can be retrieved and utilize for the current rating. Weighting of all atributes can be easy modified harmonizing to the users penchant, therefore the effectivity of this theoretical account is still really much depends on the experience and cognition of users. Manoharan [ 32 ] proposed a subcontractor choice method utilizing Analytic Hierarchy Process ( AHP ) based on 29 questionnaires collected from contractors involved in building undertakings located at Putrajaya, Malaysia. It is an Adept System to help the chief contractors in doing their determination by utilizing pairwise comparing. The determination shaper will necessitate to do their ain opinion on the comparative importance of each component with regard to the elements at a higher degree. Argument might happen when the opinion of different determination shapers are diverse. As an attempt to cut down the incidents of hold, and other possible jobs that might be originated from the jobs of choosing the incorrect sub-contractor, this survey aims to spread out the sample of survey as suggested by Manoharan [ 32 ] in the attempt of create an more dependable and applicable sub-contractor choice theoretical account.Management of SubcontractorChoosing the right subcontractor does non vouch the success of a building undertaking. Coordination and monitoring of subcontracted work during the building phase is indispensable. Ko et Al. [ 33 ] developed a Sub-contractors Performance Evaluation Model ( SPEM ) by using Evolutionary Fuzzy Neural Inference Model ( EFNIM ) . Subcontractors were evaluated by field overseers harmonizing to the types of subcontract. Different rating factors were adopted for different subcontract to accomplish just rating. Albino & A ; Garavelli [ 13 ] proposed a evaluation system for direction of subcontractor by utilizing nervous web. An application instance related to the rating of possible subcontractors viing for a command has been used to demo the practical execution of this nervous web. In accessing the rival subcontractors, the determination shaper have to see five chief parametric quantities, viz. monetary value decrease, clip decrease, technical/qualitative feature of the command, contractual dependability of the rival, and direction accomplishments of the rival. The web will suggest a suited subcontractor based on old determinations made by the expert. Therefore, illustrations of old determinations need the expert to be inserted into this nervous web. Dainty et Al. [ 34 ] focused on supply concatenation ‘s direction from the position of subcontractor. The function of subcontractors in UK building industry is explored and followed by proposal of a model for turn toing current barriers to provide concatenation integrating.DecisionSubcontractor has become a great topic to all the practicians in building industry due to the common pattern of subleasing building works into smaller bundles in building industry. Effective subcontractor choice and monitoring which can minimise the job would find the success of building companies. Problems of subcontractors, if ignored, can do an huge impact to the building undertaking, and can widen into the operation of the general contractor ‘s administration. Therefore, attending shall be given to the issues of subcontractor, which is the chief participant in about all the building undertakings.

Benefits of Social Media

Did you know that it has been proven that using social media makes people happier than spending time with family, sporting events, or having more money? (THE GUARDIAN, 2014). The rise of social media usage in modern society, particularly amongst young people, has raised concerns among many commentators about the risks and disadvantages of this type of communication. With more and more people choosing to spend large quantities of time communicating via site such as Facebook, Twitter and Instagram, critics of social media question the privacy, security, and usefulness of social media to modern society. There are both benefits and disadvantages to the increasing use of social media in our modern society. However, despite the very real disadvantages and dangers, research has indicated that social media has real benefits for modern users. Social media carries definite and proven risks for users; however, it can also be enormously beneficial. Social media has been criticized as harmful to the communication skills and benefits of real, face-to-face interactions (READING EAGLE, 2012); because social media encourages virtual communication, it can be seen as impersonal, superficial, and lacking in true empathy. However, research has also indicated that using social media makes people happy. In a study that examined a number of situations such as having more money, spending time with family, and sports events, social media was shown to be the activity that rated highest as making people happy (THE GUARDIAN, 2014). It is likely that this is a direct result of the feeling of inclusiveness and connectedness that social media creates for users, who feel that they can be heard and involved through the use of social media; it may also be a result of the fact that social media facilitates many of the other factors seen to make people happy. At the same time, social media has been criticized as harmful to the communication skills and benefits of real, face-to-face interactions (READING EAGLE, 2012). It is more accurate, however, to say that social media has changed the ways in which people communicate with one another, allowing faster and more informal and impulsive communication. Research has shown that, for businesses in particular, this change in communication methods has resulted in benefits for users in both economic terms and in terms of connectedness to others (THE SOCIAL SAVIOR, 2015). Social media makes it easier for individuals to connect to one another, but also for individuals and groups to communicate effectively, making it easier for messages and ideas to be shared widely and collectively. Communications via social media, for example, can lack security and are vulnerable to invasions of privacy because of their public nature (READING EAGLE, 2012). Outweighing these disadvantages, however, is the fact that different studies have also shown that social media can help to equip young people with a range of valuable life-skills. These benefits occur as a result of the constant practice at communication it encourages (THE WASHINGTON TIMES, 2009). By being so constantly connected to the public, young people have the opportunity to explore and challenge social conventions, develop new interests and technical abilities, and develop their personal sense of identity (THE WASHINGTON TIMES, 2009). These skills help to keep society cutting-edge and progressive, and also help prepare the next generation for life, work, and society. As can be seen, therefore, social media carries definite and proven risks for users; however, it can also be enormously beneficial. It cannot be denied that using social media carries certain risks to security, privacy and personality. However, the benefits that accrue from appropriate use of social media can be seen to outweigh those risks extensively. References

Modern Business in Comparative Perspective Essay - 6

Modern Business in Comparative Perspective - Essay Example Theorists such as Krugman, Chandler, and Rugman have developed theories that eliminate the weaknesses of the diamond model. According to Porter, he argues that the success of a nation is dependent on the prosperity of its firms. The nation acts as home base essential for an organization’s economic growth and provides competitive advantages. Porter uses the Diamond concept in determining economic growth rate of a nation. The Diamond concept offers a concept of understanding firms and their management of resources. It also gives the competitive advantages of different businesses in a nation. The first attribute is the factor condition, which is crucial to organizations growth. This attribute helps in improving cluster structure. The cluster structure involves the relation between customer, skill, technology, and distribution of products. These clusters are vital in attaining economic success at a national level. – example ? The Italian tile industry gained competitive advantage because of the cluster structure of the business. Organizations in the industry relate well with customers and they have workers who have essential skills of producing the product. The industry has also succeeded because of the use of the kiln technology, which helps in minimizing the cost of energy used to produce tiles. The industry developed this technology after the oil crisis of the 1980s, which motivated companies to develop new ways of remaining competitive. The second attribute is demand conditions, which concerns with home market nature such as home demand influence. The home demand can be affected by customer’s wants and needs (e.g local demand of product). The domestic demand plays a significant role in shaping an organization’s innovativeness and ability to upgrade, which are vital in determining breakthrough of the organization in the national market. – example? The wine producing industry in France has developed

The Student Motor Company Case Study Example | Topics and Well Written Essays - 1000 words - 1

The Student Motor Company - Case Study Example In order to regain market prominence, the Student Motor Company launched a subcompact car Zinger. The concept of Zinger was approved and the study was conducted under the supervision of the management to maintain the code of ethics of the business. The research and development and preproduction testing of the automobile usually take 43 months but for Zinger it was just above 24 months. As Zinger was a rush project, design was given more importance than the mechanical aspects which is the major concern of the manufacturing firm. This act of the management demonstrated a lack of research and ignorance of quality. The crash test of Zinger displayed few issues which were to be resolved by the management for the safety of the people. It was noticeable that a moving barrier at 21 miles per hour caused the fuel neck to be torn from the tank which caused fuel leakage. This spilled fuel could enter the driver’s chamber causing fire to ignite, this was because of defect in the engineeri ng design. The crash test demonstrated that the gasoline tank can cause fire and turn the car into flames causing damage to the society. Moreover, the Zinger was not meeting the standard of emission which would pollute the environment and cause severe damage. The company did not follow the ethical practice of the business as it launched the product in the market with manufacturing defeats. The director of the company claimed that the improved design with more safety standards would increase the cost of the car and would not be able to meet the basic requirements of the people. The management knew the facts that the launch of the car could cause death and have a negative effect on the society but to regain its market share it launched Zinger with the lingering defeats. This was an unethical practice followed by the company which caused loss of life and severe damage to the individual in the car due to the fire (Fall 1-4). The stakeholders of the manufacturing firm are Mr. I.M.Good, t he Vice President of Car Engineering, Mrs. Lovely the group Vice President of the car engineering and Student Motor’s Product Planning Committee member. The production of the Zinger and the fault were known by the committee member; hence the code of ethics was not followed by the company (Fall 1-4). QUESTION 2 The ethical issues faced by the company created a negative impact in the market. The ethical issues faced by the company could have been resolved by following the basic ethics of the business. The first aspect which the company could have done was to focus more on the research and development of the subcompact car Zinger, before launching it in the market. Furthermore, the design should not have been the main area of concern but the technicality should have been the main focus. The committee member could have stopped the production of the car and stalled its sale in the market, when the preproduction test displayed several issues which could cause death. If the company would have used their ethics and sense of responsibility and stopped the manufacturing of the defective products, the life of succumbed person could have been saved. The management was aware of the consequences of the Zinger car but did not take any preventive measures to stop such unethical practices. The second ethical alternative could have been to maintain the standard of emission as indicated by Environmental Protection Agency (EPA). The maintenance of the emission level is the responsibility of the manufacturer. The company violated the rule and launched the car without maintaining the standard. This act was a fraudulent act from the management point of view as the people would get to know about the emission after a year. The maintenance

How Executive Females Sustain their positions Research Paper

How Executive Females Sustain their positions - Research Paper Example Rather the fact is that women of European and American countries also face gender discrimination in almost all fields of life. In this paper, we will discuss the challenges that female executive face when trying to sustain their positions. The paper will also include the methods or techniques that females executives use to sustain their positions which they reach as the result of their commitment, hard work, and dedication. Challenges for Female Executives Female executives come across many challenges in their struggle towards reaching a higher position in the firm where they work (Wipperman, 2010). Their experience of gender discrimination starts even before they are actually hired for any particular position and continues till the last day of their job. For example, they face gender discrimination during recruitment process when HR executives prefer to hire male employees rather than females. The reason behind this is that HR executives consider male employees more productive and d edicated as compared to females employees. Therefore, most of the times they reject women’s job application at the earliest stages of recruitment without any logical reason. And even if a female gets a chance to work for some company, she faces discrimination at every stage of her progress towards higher ranks. For example, in cases where a female and a male employee are in the seniority list and the time occurs to promote one of them to the next rank, the HR department usually promotes the male candidate even when the performance of the female candidate is better than her male colleague. These examples show that female employees face severe discrimination at almost every stage of their job life. A very little percentage of women get the chance to attain higher positions in companies where they work (Francls & Penrose, 2011). Experiencing a male-dominated work culture and getting suitable promotions is not easy for female employees (Berneke & Strella, n.d.). Some of the main challenges that female executives face in sustaining their job positions include external male pressure, balancing work with family, and the need to show skills required for higher positions. Let us discuss these challenges in some detail, as well as the ways female executive employees overcome these challenges. External Male Pressure One of the main challenges that female executives face is the external make pressure. External male pressure refers to the overall male dominant job politics which is aimed towards bringing men forward in every job position. Although such politics is mainly played between male employees to snatch each other’s positions to reach higher ranks, but when a female employee reaches a top position by chance, then all efforts are geared towards getting the position back from that employee because the general perception in the minds of men is that higher positions are only for males and that women are not supposed to run organizational system. To deal wi th such situations, female executives usually show more commitment and dedication with their assigned roles in order to show that they are well-suited for their current positions, as well as to convince higher authorities that they can carry out their job responsibilities effectively. It has been noted that women at higher positions have more positive job attitude and are more sincere with the job work as compared to men. The reason behind this is that women are more caring and responsible by nature and when some big

Criticize the Cosmological Argument against Atheism Essay

Criticize the Cosmological Argument against Atheism - Essay Example It is also true because science and common sense has confirmed that something cannot come into existence from nothing. The premise also states that the reason why no one has seen something come into existence from nothing is proof that there is a cause for things to come into being (Rutten 45). The first premise has an intuitive appeal. It states that whatever comes into existence has a cause. The cause is what creates something. This means that the universe was impelled by a natural inclination. This is true because nothing in this world has ever come into existence out of nothing. This rebuttal tries to prove that there is no existence of God and that everything happened from nothing. However, supporters of the first premise argument object this rebuttal. The main response to this rebuttal is through the argument that all things which have a beginning in their own existence do have a cause. This means that God was not created. Unlike the universe, God did not come into existence. He has always existed even before the world came into existence (Craig 56). The second premise explains that the world began to exist. This means that the existence of the universe has a beginning. This is supported by the fact that the universe keeps on expanding and growing. The universe has over the years continued to grow and expand from an enormously dense and extremely hot state (Craig 65). This suggests that the universe started from something and continues to grow. However, the premise can be considered to be false due to one main assumption. The assumption is that it’s easy to also take into consideration that the universe, just like the initial cause, has always been in existence and continues to exist. This assumption also puts into consideration that the universe goes through an everlasting cycle of contraction and expansion. A

Health Care Insurance Essay Example | Topics and Well Written Essays - 500 words

Health Care Insurance - Essay Example Insurance are bought because it serves as a protection for people against diseases especially those that are fatal, extremely disabling and from painful medical conditions as well as the crippling cost of their treatment. In a way, insurance is also saving for the future for an individual and his family who is concerned of health risks. This is a major reason that drives people to purchase health insurance. Other considerations include the variables defined by economic theories such as rational choice theory, wherein costs and benefits are assessed to achieve the best trade-off in the economic exchange. The degree of importance attributed to health both by the public and the state makes health insurance different from other types of insurance that people pay for their properties such as cars and houses. The insurance involve health and well being of people. Pauly explained that in considering potential insurance coverage of two risky prospects with the same expected value, the person attaches more value to the coverage with lower probability but higher loss-event, sacrificing premiums so that money can be funneled to the insurance that means more to the individual (p.657-658). There is also a moralit y aspect in being able to contribute resources, which can be allocated to help care for those who truly need it (Getzen, 2010, p.50). In the United States, there is no national insurance coverage. This has been the case since insurance plans were introduced in the country in the past. Because of this, the private insurance companies have flourished. Government involvement in the industry only came after the Medicaid and Medicare were established in 1965 - two federal funded programs that provide affordable insurance to the needy. Today, healthcare coverage became a national priority. President Barack Obama has pushed for a universal healthcare coverage, which

Is regulation really necessary, or can all the benefits claimed for it Essay

Is regulation really necessary, or can all the benefits claimed for it be achieved through the promotion of competition alone - Essay Example National governments may regulate for a variety of reasons, including re-election and influence from economically powerful houses (Baldwin, Cave, and Lodge, 2012:16). Governments may also technically justify regulations, thus the general assumption that the regulation was in the context of public interest. However, most rationales presented are instances of market failure, thus regulation is initiated, as the uncontrollable market will produce results or behaviors against public interest. Other scenarios may present issues of market absence, or an ineffective market. One of the advancing and developing industries in the global economy is information and communication technology (ICT). The rapid growth of ICT presents concern over regulation and the possibilities of eliminating market failures, thus the rise of such regulatory bodies like the Federal Communication Commission in the US. In summary, regulation is better than competition in safeguarding public interest. Among the theory favoring regulation, include public interest theory, private interest theory, and interest groups theory. According to the public interest theory as argued by Baldwin, Cave, and Lodge, in their 2012 publication, the rationale behind regulation is to benefit and protect the public at large. The theory capitalizes on potential market failures such as monopolistic powers, externalities, asymmetric information, and strategic behaviors. It thus creates the ideology that consumers need protection from market failures and business abuses, with the assumption that regulation serves the best interests of the public through restricting potentially harmful business behaviors (Baldwin, Cave, and Lodge, 2012:164). The interest groups theory suggests that there is need for regulation for the interests of stakeholders, while the private interest theory seeks to safeguard the interest of private inte rest groups in regulation.

Sinusitis Care Plan Essay Example for Free

Sinusitis Care Plan Essay This therapeutic care plan will utilized the â€Å"I can treat and prescribe framework† to ensure that appropriate patient treatments are selected using a step by step approach, including assessment integration, drug and/or disease related problems, therapeutic goals, therapeutic alternatives and indications, plan of care and evaluation (OPHCNPP, 2012). By going through each step of this framework, and including or excluding treatment options based on individual patient factors and strong clinical evidence, this clinician will arrive at the most suitable treatment plan for the patient. H.K (32 year old male) presented with persistent facial pain for 7 days. He reported having a headache (6/10 on a pain scale) upon bending forward and awakening, occasional tooth pain, no nasal drainage, and no cough. H.K denied fever or chills but admitted to feeling â€Å"run-down†. His past medical history included varicella zoster at age 5 years, seasonal allergic rhinitis (pollen), viral respiratory tract symptoms 2 weeks ago (now resolved), and no recent antibiotic use over the past 3 months. He is married with two children who are not in daycare (ages 8 and 9). H.K is a supermarket manager, non-smoker, and denied substance abuse. The patient reported having private prescription drug coverage but was only taking Advil cold and sinus (2 tablets orally every 6 hours as required) with good effect. H.K’s vitals were taken (temp. 37.5 °C tympanic, HR 74 reg., R 12 reg. and equal). His head and neck examination revealed that his sclera were clear and his pupils were r ound, reactive to light with accommodation. There was tenderness to palpation of the frontal and maxillary sinuses. Transillumination of the right and left maxillary sinuses revealed an opaque surface. His nares were erythematous and edematous with no obvious discharge. There was cobblestoning of the pharynx with slight erythema. His tonsils were two plus in size with no exudates. His neck examination revealed the absence of lymphadenopathy, the thyroid was non-palpable, and his chest examination revealed clear lung fields. The diagnosis of acute sinusitis was made based on H.K’s presenting signs and symptoms. The two most common predisposing events for acute bacterial sinusitis are acute viral upper respiratory infections and allergic inflammation (80% and 20% of bacterial infections, respectively) (Desrosiers et al., 2011). Complications of sinusitis are very rare and are estimated to occur in 1 in 1,000 cases (Hwang, 2009). In complicated sinusitis, the orbit of the eye is the most common structure involved and is usually caused by ethmoid sinusitis (Hwang, 2009). Patients who present with visual symptoms (diplopia, decreased visual acuity, disconjugate gaze, difficulty opening the eye), severe headache, somnolence or high fever should be evaluated with emergent care suspected (H.K had none of these symptoms) (Hwang, 2009). Most adult patients diagnosed with acute sinusitis become well or nearly well after 7 to 10 days, but 25% are still symptomatic after 14 days (Worrall, 2011). H.K had no untreated medical conditions contributing to his acute sinusitis (not pollen season). A primary health care nurse practitioner can effectively diagnose, treat and manage adults who have symptoms like H.K according to the Nurse Practitioner Practice Standard of Ontario (CNO, 2011). His condition was not life threatening and did not necessitate a referral to a physician, specialist or transfer of care. H.K was taking Advil cold and sinus, a drug that was appropriately dosed (1-2 tablets orally every 6 hours as required to a maximum of 6 tablets in 24 hours), which is clinically indicated for sinus pain in adults and is not too complex (CPA, 2013). This drug was deemed safe for him after a review of contraindications, including hypersensitivity to the agent, nonsteroidal anti-inflammatory drug-induced (NSAID) asthma or urticartia, aspirin triad, pre-operative coronary bypass surgery, coronary artery disease, monoamine oxidase inhibitor use within 14 days, uncontrolled or severe hypertension, and urinary retention (Epocrates, 2013). For H.K, the oral route of medication administration was most appropriate, the least invasive and the easiest way for an adult to take drugs (Brophy et al, 2011). Advil cold and sinus is not a cytochrome P450 system inhibitor, which is the main (or partial) cause for large differences in the pharmacokinetics of other drugs (Rx Files, 2012, Epocrates, 2013). The patient was not taking borrowed prescriptions, using drugs from previous occurrences of the condition, or experiencing any adverse drug events/reactions to Advil cold and sinus. Also, he was not being double dosed or experiencing therapeutic duplication of drugs belonging to the same pharmaceutical class. H.K had no untreated medical conditions (other than his new acute sinusitis), was not taking drugs prescribed by other clinicians and there were no other factors (communication errors, non-adherence, financial restrictions) influencing his ability to receive medication. Antibiotic therapy should be reserved for patients with acute bacterial sinusitis as defined by a complete history and physical examination (AMA, 2008). A â€Å"wait and see† approach has been suggested in recent Canadian guidelines as a means of differentiating bacterial sinusitis from a viral respiratory tract infection (Desrosiers et al., 2011). Initiation of treatment should take place 7 to 10 days after persistent symptoms or when signs compatible with acute sinusitis occur (Desrosiers et al., 2011). Since H.K’s facial pain had lasted for 7 days, the decision was made with the patient to treat. Goals of care were established (with the patient) including maximizing symptom relief (especially drainage of congested sinuses), eradication of infection, and prevention of re-occurrence and complications (Fryters Blondel-Hill, 2011). Five drug choices were selected and scrutinized as potential treatment options for H.K, including first and second line therapies (appendix 1) (ARP, 2012). The primary bacterial pathogens involved in the development of acute sinusitis for adults are Streptococcus pneumonia and Haemophilus influenzae (AMA, 2008). Canadian antimicrobial resistance data of S. pneumoniae describes that penicillin resistance rates range from 14% to16% in Central Canada (Powis et al., 2004). Amoxicillin is a first line drug therapy that remains active against S. pneumoniae with the rate of resistance under 2% (Brook et al, 2006) and also retains the best coverage of oral beta-lactam agents against S. pneumoniae (AMA, 2008). It is available in a capsule, chewable tablet or powder for oral suspension (H.K had no dysphagia and preferred to take capsules) (CPA, 2013). Amoxicillin should not be prescribed to a patient more than once in a 3-month period (H.K had not taken it in the last 3 months) (ARP, 2012). This drug is acid resistant, rapidly absorbed after oral administration, and is stable in the presence of gastric acid allowing for adequate systemic concentr ations (H.K was not taking drugs that affect gastric acid production) (CPA, 2013). Pertinent adverse affects of the drug are diarrhea, nausea, headache, vomiting, abdominal pain, anaphylaxis, anemia, AST/ALT elevation, mucocutaneous candidiasis, rash and pseudomembranous colitis (Medscape Reference, 2013). Amoxicillin is contraindicated with anaphylaxis reaction to penicillins or cephalosporins (Epocrates, 2013). Several cautions to consider when prescribing amoxicillin to H.K include him having clostridium difficile infection, infectious mononucleosis (result is skin rash), bacterial/fungal superinfections, allergy to cephalosporins, and carbapenems, (Medscape Reference, 2013). Also, serious drug interactions include bcg/typhoid vaccine live, doxycycline, minocycline, probenecid and tetracycline (Epocrates, 2013). H.K did not have any of the contraindications, cautions, or potential medication interactions relevant to taking amoxicillin, so it was deemed safe for him to take. Amoxicillin was selected as a treatment option for H.K (appendix 1). The three times a day (500 mg) option was selected to ensure simplicity, when compared to the 875 mg twice a day option that would require H.K to take two possibility identical capsules (a 500 mg and a 250 mg), increasing the likelihood of medication error (Epocrates, 2013). A primary concern for individuals infected with H. influenzae is ampicillin resistance, mediated by the production of a beta-lactamase, which is produced by approximately 19% of the bacteria (Zhanel et al, 2003). H. influenzae remains predictably susceptible to amoxicillin-clavulanate (a second line therapy) which possesses the added benefit of stability against beta-lactamases and cephalosporins (Tristam et al, 2007). Amoxicillin-clavulanate is also effective against most penicillin-resistant S. pneumoniae (MacGowan et al., 2004). It has enhanced gram positive activity and should be used in patients where risk of bacterial resistance is high, consequences of failure of therapy are greatest, or for patients not responding to first-line therapy (DeRosiers, et al, 2011). Common side effects of this drug are nausea, vomiting, diarrhea, rash and uticartia (Poole-Arcangelo Peterson, 2013; Rx Files, 2013). Higher rates of diarrhea and other gastrointestinal side effects occur with amoxicillin-clavulanate than with amoxicillin alone (Burns et al., 2009). It is also considered a more costly sinusitis treatment (ARP, 2012; Rx Files, 2012). Amoxicillin-clavulanate was added as a treatment option for H.K (see appendix 1). The clinician selected the two times a day option (875 mg) because the clavulanic acid daily dose is less, resulting in a decreased likelihood of the patient experiencing adverse effects co mpared with a more frequent dosing schedule option such as every 8 hours (Rx Files, 2012). As a result of activity against beta-lactamase–producing H. influenza and S. pneumonae (Zhanel Lynch, 2009), cefprozil and cefuroxime axetil have a second line treatment role in acute sinusitis (ARP, 2012). With the expanded spectrum of activity, ability to achieve adequate concentrations in tissues, suitability for twice-daily dosing, favorable toxicity profile, and proven tolerability of cephalsporins, they are a safe alternative for treatment (Poole-Arcangelo Peterson, 2013). However, they have a broader range of activity and are more costly than amoxicillin (Rx Files, 2012; ARP, 2012). Second line drugs cefuroxime axetil and cefprozil were added as treatment options for H.K (see appendix 1). The 250 mg dose was selected for both drugs due to ease of use (smaller pills, easier to swallow), patient related factors (H.K was not immunocompromised) and disease related factors (H.K’s sinusitis had no complications). In beta-lactam-allergic patients, a second line therapy such as trimethoprim-sulfamethoxazole (TMP- SMX) may be substituted for penicillin (ARP, 2012). The TMP-SMX resistance reported from Canadian laboratories is approximately 14% (Desrosiers et al., 2011). Increased pnuemoncoccal and H. influenza resistance rates make TMP-SMX a less desirable agent, however it is one of the most cost-effective options for patients with financial constraints (not an issue with H.K) (ARP, 2012). The most common side effects of this drug are rash, fever and gastrointestinal symptoms (Poole-Arcangelo Peterson, 2013; Rx Files, 2012). Drugs containing sulfa (such as TMP-SMX) potentiate the effects of warfarin, phenotoin, hypoglycemic agents and methotrexate (Poole-Arcangelo Peterson, 2013). Since H.K is not taking these drugs, TMP-SMX was selected as a treatment option (see appendix 1). One double strength tablet was selected over two single strength tablets for simplicity of administration. The general approach to the non-pharmacological management of acute sinusitis requires utilizing adjunctive therapies. Decongestants, intranasal corticosteroids (INCS), antihistamines, mucoltylics and analgesics are treatment options. A decongestant may be used to reduce mucosal edema and facilitate aeration and drainage (Desrosiers et al., 2011). Oral decongestants have been shown to improve nasal congestion and can be used until symptoms resolve. (Desrosiers et al., 2011). Topical decongestants are controversial and should not be used for longer than 72 hours due to the potential for rebound congestion (ARP, 2013). INCS reduce inflammation and edema of the nasal mucosa, nasal turbinates, and sinus ostia (Desrosiers et al., 2011). INCS are minimally absorbed and have a low incidence of systemic adverse effects (Desrosiers et al., 2011). Adverse effects include transient nasal irritation, epistaxis, pharyngitis, rhinitis, headache, and changes to taste, smell and voice (Rx Files, 201 2). A Cochrane review evaluating three INCS drugs for acute sinusitis found limited but positive evidence for INCS as an adjuvant to antibiotics (Zalmanovici Yaphe, 2009). Antihistamines are often used to relieve symptoms because of their drying effect, however there are no studies to support their use in the treatment of acute sinusitis (Desrosiers et al., 2011). Guaifenesin is a mucolytic that has been used to thin mucus and improve nasal drainage, however because it has not been evaluated in clinical trials, it was not recommended as an adjunct treatment for sinusitis (Rosenfeld et al, 2007). Selection of analgesics should be based on the severity of pain. Tylenol or an NSAID given alone or in combination with an opioid is appropriate for mild to moderate pain associated with sinusitis (Rosenfeld et al, 2007). Recent Canadian guidelines suggest that limited evidence exists supporting the beneficial effects of saline irrigation in patients with acute sinusitis (Desrosiers et al., 2011). Despite limited evidence, saline therapy, either as a spray or high-volume irrigation, has seen widespread use as adjunct therapy (Desrosiers et al., 2011). Although the utility of saline sprays remains unclear, the use of saline irrigation as ancillary therapy is based on evidence of moderate symptomatic benefit and favourable tolerability (Desrosiers et al., 2011). Some additional comfort measures for patients with symptoms of acute sinusitis include maintenance of adequate hydration and application of warm facial packs. No high quality trials have demonstrated that these comfort measures are effective (Worrall, 2011). As viral infections predispose individuals to acute sinusitis, strategies (such as handwashing) that focus on patient education of reducing viral transmission help to reduce the incidence of bacterial sinusitis (Desrosiers et al., 2011). Educating patients about common predisposing bacterial sinusitis factors may be considered as a preventative strategy (Desrosiers et al., 2011). Prophylactic antibiotics are not effective in preventing viral episodes or the development of subsequent bacterial sinusitis, and are not recommended (Desrosiers et al., 2011). Also, there is no evidence that influenza or pneumococcus vaccinations reduce the risk of contracting acute sinusitis (Rosenfeld et al, 2007). Recent reviews have found limited evidence for alternative and complementary medicine (Scheid Hamm, 2004). Alternative practices that have failed to show efficacy include acupuncture, chiropractic, naturopathy, aromatherapy, massage and therapeutic touch (Desrosiers et al., 2011). Vitamin C preparations and zinc lozenges are also felt to be controversial (Scheid Hamm, 2004). Studies of zinc lozenges for the common cold have produced mixed results (Desrosiers et al., 2011). One recent meta-analysis of echinacea preparations has shown some positive effects in reducing duration of respiratory tract symptoms (Barrett et al, 1999). However, the widespread use of echnichea in the treatment of acute sinusitis is not well supported (Desrosiers et al., 2011). A recent Cochrane review found that when antibiotics were given to patients, they increased recovery time from sinusitis symptoms (Ahovuo-Saloranta, 2008). The choice of first-line treatment is based on the anticipated clinical respons e of a patient, as well as the microbiologic flora likely to be present. Also, when selecting an antibiotic regimen for H.K, the clinician considered the medication cost, medication safety profile, adverse effects, and local patterns of bacterial resistance in order to maximize therapy (Hickner et al., 2001). The recommended antibiotic regimen is specific for H.K, who did not have any intracranial/orbital complications or a compromised immune function, and has normal renal function. In the absence of drug allergies and presence of resistant organisms, amoxicillin was selected for H.K as it is a first line therapy, is generally effective against susceptible and intermediate resistant pneumococci (Brophy et al, 2011), low cost (ARP, 2012), high patient tolerability, and relatively narrow antimicrobial spectrum (Aring Chan, 2011). Factors suggesting greater risk of penicillin resistant streptococci include antibiotic use within the past 3 months, chronic symptoms present for longer than 4 weeks, and parents of children in daycare (H.K had none of these risk factors). When antibiotics are prescribed by the clinician, the duration of treatment should be 5 to10 days as recommended by product monographs (Desrosiers et al., 2011). For H.K, the clinician utilized product monographs and other evidence based guidelines for determining the appropriate duration of treatment (CPA, 2013; ARP, 2013). Based on the information and discussion presented in this paper, amoxicillin 500 mg three times a day for 10 days (CPA, 2013) was selected as the most appropriate treatment for H.K (see appendix 2). H.K was instructed by the clinician to take his medication until finished, not share it, and to store at room temperature away from moisture, heat and light (Epocrates, 2013). He was taught about the drug’s side effects and that overdose symptoms may include confusion, behavior changes, severe rash, decreased urination, or seizure (Epocrates, 2013). He was provided health teachings by the clinician, including seeking emergency medical help if exhibiting any signs of an allergic reaction (hives, difficulty breathing, swelling of the face, etc.) or experiencing serious side effects (white patches/sores inside his mouth/lips, fever, swollen glands, rash, itching, joint pain, pale/yellowed skin or eyes, dark colored urine, fever, confusion/weakness, severe tingling, numbness, pain, muscle weakness, easy bruising, unusual bleeding, purple/red pinpoint spots under his skin) (Epocrates, 2013). H.K was provided health teachings regarding reducing the risk of contracting viral infections through hand washing techniques. Complementary therapies, alternative medicines, comfort measures, saline prophylactic antibiotic usage and vaccines were not recommended to H.K. He was also instructed about the role these treatments play in acute sinusitis treatment. Only evidenced-based adjunctive therapies as described in this paper have been selected for H.K, including INCS therapy (see appendix 3), analgesics (Advil cold and sinus) and oral decongestants (Advil cold and sinus). H.K agreed to this treatment plan. Based on H.K’s history and physical exam findings, a follow-up examination would be required if no improvement is seen within 72 hours of antibiotic administration, as this could indicate treatment failure (Derosier et al, 2011). The patient was advised to return in 72 hours if there were no improvements in symptoms. He did not return to the clinic for follow-up. If H.K had deteriorated at any time, the clinician would have reassessed for acute complications, other diagnoses and adherence to treatments (Derosier et al, 2011). If H.K experienced a type 1 hypersensitivity reaction to amoxicillin at any time, other pharmacological options would have been considered. A phone call was placed one week after H.K’s medical visit to conduct a post-visit evaluation, and he reported that his symptoms were nearly resolved (pharmacological and non-pharmacological therapy evaluation). Since H.K demonstrated signs of clinical improvement, a follow-up visit or possible referral to an otolaryngologist was not required (Fryters Blondel-Hill, 2012). The original goals of care for H.K were met. He stated that he was able to manage his symptoms with the treatment plan, was grateful that no complications were experienced, and was more knowledgeable about the prescribed drugs and future prevention strategies. H.K was satisfied with his healthcare experience (self-report) and was able to verbalize non-pharmacological therapies and apply them to his situation. When faced with a similar patient in the future, the clinician will ensure that the â€Å"I treat and prescribe framework† is utilized, as it is a valuable tool for ensuring patient specific treatment. Professional feedback from the course instructor/preceptor will also be integrated into future treatment plans.

Staphylococcus Aureus: Structure and Functions

Staphylococcus Aureus: Structure and Functions Introduction 1.1 Staphylococcus aureus Staphylococcus aureus is an opportunistic yet versatile pathogen that can infect almost all types of tissue in the human body. 33-50% of healthy individuals were reported to be S. aureus carriers. The diseases resulting from S. aureus infection range from superficial infections; invasive infections such as endocarditis to the life threatening septic shock and toxic shock. The presence of foreign material greatly increases the risk of infection by providing a base for attachment and biofilm formation. S. aureus appears as clustered gram positive cocci under the microscope. Criteria used to identify this organism include the production of golden pigment on nutrient agar; being positive for coagulase; mannitol fermentation and the production of deoxyribonuclease. The virulence of the infecting strain and the nature of the host immune response are important determinants for the outcome of severe S. aureus infection . 1.1.1 S. aureus genome and regulation of gene expression S. aureus has a 2.8-2.9 Mbp circular genome. House-keeping genes and genes associated with central metabolism and some virulence determinants (e.g. protein A) are highly conserved among strains and make up the majority of S. aureus genome. The rest more variable regions mainly consists of mobile elements such as pathogenicity islands (SaPI, 7 identified), genomic islands (ÃŽ ½SaÃŽ ± and ÃŽ ½SaÃŽ ²), Staphylococcal chromosomal cassettes (SCC) and bacteriophages. S. aureus expresses an array of adhesins, immunomodulatory molecules; anti-inflammatory proteins and as many as 30 toxins to invade, evade and cause host tissue damage. Many of the virulence factors discussed below are encoded by genes located in the variable region. Their expression is under the control of a complicated and interconnected regulatory network . Four main gene regulators have been identified, including the two component regulatory system (agr, sae); the transcription factors (SarA and its homologous); the nutrient regulated CodY regulator and alternative transcription factor ÏÆ'B. agr is an auto-inducible quorum-sensing system, promoting expression of extracellular virulence factors and down-regulating cell surface proteins. ÏÆ'B has been shown to participate in the general stress response, and may be involved in antibiotic resistance; pigmentation; biofilm and micro-colony formation (referenced in ). Many surface proteins/adhesin have been shown to be positively influenced by ÏÆ'B, while the expression of most exoproteins and toxins were down-regulated. Activity ofthe agr system is influenced by other gene regulators and may be regulated by cell density. The transcription of agr components were found to be promoted by SarA and gene products of the sar locus and repressed by CodY. To add up the complexity, transcription o f the Sar locus was controlled by three promoters that can be differently activated during in vitro growth. One of these promoters was demonstrated to be ÏÆ'B dependent . It is generally regarded that exponential growth in vitro is correlated with the colonization phase of infection. Correspondingly, genes encoding surface proteins were found to be expressed earlier, starting during the transition from stationary to exponential growth while the expression of secreted proteins started at late-exponential growth phase. The in vivo situation of infection is likely to be more dynamic. Different stimuli trigger combined and coordinated action of the regulatory network, reflecting the particular state of bacterial growth, host defense and environmental nutrition. For example, phagocytosis by neutrophil triggered differential expression of 21.8-39.1% of S. aureus genes â€Å"at any time† following the event. The suppressive effect of CodY on S. aureus virulence factors lead to the possible suggestion that S. aureus may maintain its virulence factor to low level to ‘co-exist harmlessly with the host until a invading opportunity arise. In any case , it would be interesting to see how host immunological activity ‘feedback on S. aureus regulation of its virulence factors, especially immune evasion molecules. 1.1.2 Antibiotic resistance The rapid spreading of antibiotic resistant S. aureus strains through human communities presents a major challenge for conventional treatment. In 2005, it was reported that methicillin-resistant S. aureus (MRSA) infection caused more death than AIDS in USA. S. aureus demonstrated amazing ability to â€Å"co-evolve† with the development of antibiotics. The first generation penicillin uses ÃŽ ²-lactam to bind penicillin-binding proteins (PBP, bacterial transpeptidase) and inhibits bacterial cell wall synthesis. S. aureus resists this class of antibiotics by producing ÃŽ ²-lactamases (aka penicillinase) that cleaves ÃŽ ²-lactam. Second generation of penicillin, such as methicillin was developed. The structure of their ÃŽ ²-lactam has been modified to resist ÃŽ ²-lactamases. S. aureus soon acquired the mecA operon that encodes a modified PBP (PBP 2a), which showed reduced susceptibility for ÃŽ ²-lactam and thus granted resistance to all ÃŽ ²-lactam containing antibiotics. mecA is located on the staphylococcal chromosome cassette mec (SCCmec), a mobile genetic element that allows horizontal transfer of mecA between strains. MRSA infection shows increasing prevalence in all continents, primarily in healthcare-environments (HA-MRSA). Alarmingly, these strains have been shown to exhibit resistance to other types of commonly used non-lactam antibiotics such as ciprofloxacin and erythromycin. Vancomycin, a peptidoglycan polymerization inhibitor, is now considered as the last-line antibiotics for MRSA treatment. However, strains of vancomycin-intermediate S. aureus (VISA) have emerged. Notably, these strains have developed thicker cell walls that require higher concentrations of vancomycin to be effective (minimal inhibitory concentration MIC over 4ug/ml). A vancomycin resistant S. aureus (VRSA) strain has been reported recently (MIC >32 ÃŽ ¼g/ml). This complete resistance is most likely due to the horizontal transfer of the vancomycin resistant gene (VanA) from En terococcus faecalis. Development of effective new antibiotics against S. aureus has met with only limited success, urging the development of alternative therapies based on better understanding of the pathogenicityof S. aureus . 1.2 Adhesin / ECM interaction as key to S. aureus colonization/invasion Colonization is always the first step in bacterial infection and is an important component in pathogenesis. The wide range of tissues that S. aureus can infect reflects its ability to adhere and therefore colonize many different biological niches. S. aureus is now recognized as an invasive organism, targeting non-professional phagocytes such as keratinocytes, epithelial cells, endothelial cells and osteoblasts. The tasks of initial colonization and invasion are assisted by S. aureus surface anchored and secreted adhesive molecules known as MSCRAMM, microbial surface components recognizing adhesive matrix molecules and SERAM, secretable expanded repertoire adhesive molecules. The majority of MSCRAMM and SERAM bind extracellular matrix (ECM) proteins such as fibrinogen and fibronectin. In general, the interaction with ECM proteins is regarded as providing a ‘foothold for S. aureus to establish and to exacerbate infection. However, it has been reported that in some animal models l oss of fibronectin binding proteins (FnBPs) led to an increase in bacterial virulence, indicating a role of the ECM protein in limiting bacterial dissemination or enhancing bacterial clearance. Due to overlap in target specificity; functional redundancy and the difference in experiment settings, the exact contribution of each isolated staphylococcal adhensin protein remains ambiguous. Nevertheless, fibronectin (Fn) and fibrinogen (Fg) are the most popular targets of known S. aureus adhesins. The interaction between FnBPs and Fn is thought to play a key role in S. aureus internalization by non-phagocytic cells, as FnBP-coated latex beads and non-invasive bacteria expressing FnBPs were readily taken into the human cells (293 cells). Internalization provides several benefits for the bacterium: firstly, protection from host serum defense mechanisms and antibiotics ; secondly, access to nutrient-rich environments after escape from phagocytic vessels; thirdly, facilitating the crossing of the endothelial/epithelial layer and spreading of the infection; and lastly, establishing intracellular bacterial reservoirs for recurrent infection. S. aureus produces two related FnBPs (namely A and B) that contain almost identical Fn-binding domains in the close proximity to their cell-wall-spanning domain. The Fn-binding repeats of FnBPA were crystallized in complex with the N-terminal F1 modules of Fn. FnBPA peptide is inserted along the triple-stranded ÃŽ ² sheets of the Fn F1 module to form an antiparallel tandem ÃŽ ² zipper. Since the C-terminus of Fn interacts with ÃŽ ±5ÃŽ ²1 integrin that are expressed on most host cell surfaces, S. aureus can attach to the host cell through a Fn bridge. The attachment was shown to trigger the accumulation of actin and focal-contact-associated proteins (e.g. tensin) at the bacteria contact site and initiate internalization in a protein tyrosin kinase FAK-dependent manner. It was predicted that one FnBP can bind six to nine Fn molecules. This multivalent interaction was suggested to be important in mediating internalization . The bindings of Fg by the clumping factors (ClfA and ClfB) and FnBPA are mediated by a shared protein structure called the A domain and by a â€Å"dock, lock and latch† mechanism. Interestingly, Clf A is expressed during stationary phase and binds to the ÃŽ ³ chain of Fg. ClfB is expressed at the exponential growth phase and binds to the C-terminus of Fg AÃŽ ± chain. This portion of Fg has been reported to be involved in the coagulation process and wound healing . Fn and Fg interactions have been blamed particularly in S. aureus wound infection and infective endocarditis in humans. Fg binding alone could initiate experimental endocarditis in mice and has been correlated with valve colonization. However, cell invasion and persistence of the infection only occurred when the Fn-binding ability was enabled (via FnBPs). Both interactions were statistically correlated to disease severity. Binding to Fg and Fn simultaneously significantly accelerated the rate of internalization into cultured endothelial cells. In this regard FnBPA that is capable of binding both proteins may play an important role in establishing endocarditis . Platelets accumulation on the heart valve is another critical factor for the development of infective endocarditis. S. aureus-induced platelet aggregation is a complicated and multifactorial process and was suggested to be dependent on Fg or fibrin. FnBPA, ClfA, ClfB and SdrE (serine-aspartate repeat protein) were shown to be able to cause platelet aggregation independently of other S. aureus surface proteins. ClfA displayed the strongest aggregation effect among the last three. SdrE required the presence of plasma to cause aggregation, although the mediator was not identified. ClfA was proposed to interact with platelet indirectly through an Fg bridge or directly with platelet surface protein p118. Other studies have argued that ClfA-specific IgG also participated in platelet activation by cross-linking ClfA to platelet FcÃŽ ³RIIa receptor . 1.3 S. aureus toxinsdirect damage of host cells S. aureus produces a range of cytotoxins, including the ÃŽ ² barrel pore forming toxin (e.g. ÃŽ ± hemolysin); the two component pore forming leukocidins and the exfoliative toxin. Besides the effects of reducing viable phagocytes and weakening host immune system, S. aureus cytotoxins are currently believed to contribute to bacterial dissemination. Lysis of host cells might also provide nutrients for proliferating bacteria, especially iron from hemolysis . These toxins have different prevalence in different diseases. Exfoliative toxin (ET) operates at the epidermal layer of the skin and causes staphylococcal scalded-skin syndrome. ET-A acts as serine protease and specifically cleaves Desmoglian-1 (Dsg-1). Dsg-1 is a cell-cell adhesion molecule expressed on epidermal keratinocytes. Cleavage of Dsg-1 disrupts the superficial layer of epidermis and helps bacterial invasion. ÃŽ ±-hemolysin (Hla) is strongly implicated in S. aureus lung infections. Active and passive immunization of Hla strongly protected mice against S. aureus pneumonia. Hla is released as a water soluble monomer and oligomerises on the host cell membrane to insert the hydrophobic stem domains. Seven Hla monomers are required to form a pore which eventually leads to cell lysis. At sub-lethal concentrations of Hla, host cells produce pro-inflammatory cytokines like IL-8; IL-6; vasoregulators (PGI2, PGE2 and thromboxane), which could have detrimental systemic effect. The exp ression of twenty S. aureus virulence factors were disrupted individually or in combination and the virulence of the resultant deletion mutants were compared in a mice pneumonia model. Deletion of argA, which encodes a component of the arg gene regulation system, resulted in almost complete loss of virulence. Only the Hla deletion mutant produced comparable effects, indicating the importance of Hla in causing lung tissue damage. Human neutrophils can resist Hla lysis but these cells are targeted by Leukocidins. Leukocidins are thought to act in the similar way as Hla. Among the leukocidins, Panton-valentine leukocidin (PVL) is found in all CA-MRSA (community acquired-MRSA) isolates and strongly associated with CA-MRSA infection. However in mouse models of abscess, sepsis, and pneumonia, the severity of diseases caused by PVL- deletion strains were not significantly different from that caused by the wt strains. More surprisingly, PVL-expressing S. aureus strains did not lyse human ne utrophils better than that without PVL. However, it is not clear how these experimental conditions resemble the amount and time of PVL production during infection in human. Another significant problem is that PVL might be human specific and might not work in mice. Nevertheless, a new class of leukocidal molecules, the ÃŽ ± type phenol-soluble modulin (PSMÃŽ ±), was produced at a considerably high level by CA-MRSA. They were shown to contribute to the increased neutrophil lysis, skin lesion formation and mortality rate of experimental animals caused by CA-MRSA infection . 1.4 Interaction of S. aureus with host immune system 1.4.1 Brief overview of host defense against S. aureus Host defense against S. aureus mainly relies on the innate immune system, in particular, neutrophil mediated killing. The integrity of skin and mucosal layer is the first line of defense against invading bacteria. They also encounter antimicrobial substances released by epithelial cells and phagocytes (e.g. defensins; cathelicidins and lysosome). Defensins and cathelicidin are positively charged antimicrobial peptides that could permeate the bacterial membrane. Lysozyme is produced by many cell types and secreted into various tissues. It cleaves bacterial cell wall peptidoglycan at ÃŽ ² 1-4 glycosidic linkage between N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG). Innate pattern recognition receptors (e.g. Toll-like receptor 2) and immunoglobulin also detect the presence of S. aureus. The latter is recognized by C1q and initiates the complement classical pathway (CP) or directly activates phagocytosis through Fc receptor expressed on neutrophils or monocytes. The human comp lement system is discussed in more detail below. One outcome of complement activation is the production of anaphylatoxin C3a and C5a. Together with formyl methionine peptides produced by bacteria, these chemoattractants are sensed by their receptors expressed on leukocytes and attract leukocytes to the sites of infection. Leukocyte recruitment is accomplished through highly coordinated interactions between adhesins on leukocytes and endothelial cells. Leukocytes change from rolling in the blood stream to firm adhesion to the endothelium and then transmigrate through the endothelial layer. Subsequent migration of leukocytes to infection sites is mediated by integrin interacting with ECM proteins. Once they reach the infection site, the phagocytes recognize antibodies or complement fragments deposited on the bacterial surface through their respective receptors. Phagocytosis then occurs. The phagosome is fused to the lysosome to form the phagolysosome for enzyme-mediated and oxygen fre e radical mediated destruction . 1.4.2 The human complement system The human complement system is a sequentially activated proteolytic cascade that involves more than 30 fluid phase and surface bound proteins. It is one of the key elements of the innate immune system that connects bacterial recognition, leukocyte chemotaxis; phagocytosis as well as adaptive immunity . Three main activation pathways are utilized to recognize foreign and danger signals. The classical pathway (CP) senses antigen bound antibody by C1q. Bacterial carbohydrate ligand is recognized by mannose binding lectin (MBL) or ficolins and initiates the lectin pathway (LP). Upon ligand recognition, both pathways use their specific proteases to cleave C4 and then C2. The resultant C4b2a (the C3 convertase) converts C3 to C3a and C3b. The Alternative pathway (AP) starts by direct binding of C3b to the bacterial surface generated by spontaneous lysis of C3 to C3b called â€Å"tick-over†. Factor B that associates with surface-bound C3b is subsequently cleaved to Bb and forms the alternative pathway C3 convertase C3bBb. The amplification loop of C3 activation is started. C3 cleavage is the central event and merging point in the three pathways. Accumulation of surface bound C3b changes the substrate specificity of C3 convertase to C5. C5 cleavage produces C5a and C5b. The latter m ediates the formation of the membrane attack complex C5b-9 (MAC), which inserts into the target cell membrane and ultimately causes lysis of target cells. C3a and C5a are powerful anaphylotoxin that trigger neutrophil homing. The overall picture of this complex system is depicted in Fig. 1.1 MASP: mannose-binding lectin–associated serine proteases. Figure adapted from Walport et al 2001 (Ref.). Three main outcomes of complement activation are: 1, chemotaxis of leukocytes via C5a and C3a; 2, C3b mediated phagocytosis via complement receptors on phagocytes; and 3, lysis of bacteria by MAC. It is also suggested by recent studies that the C3b presented on bacterial surface are critical factors for B cell activation and the production of specific antibodies. Although the MAC complex cannot function on gram positive bacteria like S. aureus, leukocytes mediated killing is critical for fighting against S. aureus infection . 1.4.3 S. aureus Immune evasion molecules 1.4.3.1 Resistance to antimicrobial substances S. aureus circumvents antimicrobial substances by three main strategies: 1, changing surface charges; 2, modifying the substrates of antimicrobial substances and 3, inactivating antimicrobial substances. S. aureus employs two enzymes to change the highly negatively charged teichoic acid in its cell wall (WTA). DltABCD (Dlt operon) adds D-alanine to WTA and the multiple peptide resistance factor F (Mprf) participates in the modification of membrane phosphatidylglycerol with L-lysine. Both modifications increase bacterial surface charges and thus reduce the attraction to the cationic defensins. dlt or MprF defective strains were killed more efficiently by neutrophil oxygen-independent killing. The former was much less able to cause arthritis and mortality in mice sepsis and arthritis models . S. aureus avoids lysozyme cell wall cleavage by modifying its cell wall peptidoglycan. O-acetyltransferase (OatA) was proposed to mediate this response. OatA catalyses the acetylation of muramic acid, which results in the addition of an acetyl group on S. aureus peptidoglycan. An oatA- strain was sensitive to lysozyme, while complementary expression of the enzyme restored its resistance . Two enzymes have been reported to directly inactivate antimicrobial peptides. Aureolysin (a metalloproteinase) could cleave and therefore inactivate cathelicidin LL-37. Staphylokinase (SAK), a secreted plasminogen binding protein, was reported to form a complex with ÃŽ ± defensin and almost completely blocked its antimicrobial activity. This activity was independent of plasminogen binding. S. aureus strains that produce SAK had a higher survival rate in vitro and higher virulence in a mouse arthritis model . 1.4.3.2 Prevent phagocytosis and opsonision 1.4.3.2.1 General anti-opsonin molecules S. aureus clinical isolates produce a capsular polysaccharide outer cell wall. Serotypes 5 and 8 of the capsular polysaccharide are associated with increased virulence. The capsule is anti-opsonic via blocking of surface deposition of opsonins and their receptor/ligand interaction. Immunoglobulins are targeted by protein A (SpA) and its homologues Sbi (S. aureus IgG-binding protein), SSL7 (Staphylococcal superantigen-like protein 7) and SAK. SpAis a 42 kDa surface anchored molecule. It has four to five IgG binding units that could interact with IgG Fc portion. This interaction presents IgG to leukocytes Fc receptor in the wrong orientation and therefore prevents recognition. In the present of IgG, strains expressing high level of SpA were shown to be more resistant to leukocyte phagocytosis than SpA-poor strains, especially when the sole source of opsonin was purified IgG. Opposite results occurred with IgG-deficient serum, indicating SpA confers protection against neutrophil through IgG interaction. Sbi contains two IgG binding sites at the N-terminal domain. The significance of the Sbi/IgG interaction remains to be fully established. SAK forms a complex with plasminogen and converts plasminogen to plasmin. Plasmin cleaves IgG and C3b deposited on S. aureus resulting in reduced recognition by phagocytes and likely impaired initiation of C1q mediated CP activation . 1.4.3.3 Complement inhibition S. aureus is now recognized as ‘a master of complement evasion. Unlike other bacteria which use host factors to ‘disguise the bacteria or inhibit complement activation, S. aureus produces a group of proteins to attack the key elements of the complement cascades. The list of anti-complement virulence factors is growing. So far, five complement inhibitors have been demonstrated and well characterized: SCIN; Efb; Ehp; SSL7 and Sbi. Interestingly, SCIN, Efb, Ehp and Sbi all use a triple ÃŽ ± helix bundle as their functional domain while their modes of action are markedly different (Fig. 1.2). SSL7 belongs to the SSL protein family. Its function will be discussed in context with other members of the family in a later section. 1.4.3.3.1 SCIN SCIN (staphylococcal complement inhibitor) is a human-specific 9.8 kDa secreted protein with a trip ÃŽ ± helix structure (Fig. 1.2) and is produced by 90% of S. aureus strains. SCIN was shown to inhibit all three complement activation pathways. In the presence of SCIN, the deposition of C3b and MAC were prevented, so was the C2b and Ba release. However the amount of surface bound C3 convertases (both forms) were increased, suggesting SCIN had a stabilizing effect on this complex. SCIN bound to surface-immobilized C3b directly and the binding site was predicted to involve the C3b MG7 and MG8 domain and the area nearby. This was confirmed by the co-crystallized SCIN-C3bBb complex. In vitro binding studies suggested the complex was likely to form in a 1:1 or 2:2 ratio. Indeed in the crystal structure, the complex appeared as a SCIN2C3b2Bb2 heterodimer that was bridged by the two SCIN molecules cross-linking the two C3b fragments. However this cross-linkage was not critical in SCIN compl ement inhibition as monomeric interaction also resulted in stable and inhibited C3 convertase. Native C3 could still associate with the SCIN-C3 convertase complex, but the production of C3b was largely inhibited, suggesting the convertase was likely trapped in a dysfunctional yet stable state by SCIN. Moreover, SCIN exerted a partial competition for factor B binding to C3b and a complete competition for factor H/C3b binding. The significance of the inhibition on factor H was not clear although reducing iC3b (inactive product of the cleavage of C3b) mediated downstream signaling could be beneficial for the bacterium. Physiologically, C3 convertase decays shortly after assembly. This disassociation is required for further cleavage of C2 and factor B. Thus SCIN functions by preventing C3 convertase decay; hindering conformational activation of C3 convertase and possibly by blocking C3b/iC3b mediated signaling . 1.4.3.3.2 Efb Efb (extracellular fibrinogen-binding protein) and the recently discovered Ehp (Efb-homologous protein aka Ecb) have been shown to inhibit C3b deposition in AP and C5 convertase activity in all three pathways. The efb gene is present in 85% of S. aureus isolates sequenced to date. Its inhibitory effects on complement mediated lysis and neutrophil activation in response to C5a have been demonstrated. The Efb complement binding domain (Efb-c) is also a triple ÃŽ ± helix huddle, although the arrangement is different from SCIN (Fig.1.2). It binds both C3 and C3b via the C3d fragment. However, which of the C3 forms is the primary target of Efb is debated. Structural-biochemical analysis suggested the binding affinity of Efb-C to native C3 was higher than that to C3b. The binding was proposed to induce conformational changes in C3 and prevent proper cleavage of the molecule. This view was challenged by Jongerius et al based on the observation that C3 cleavage was not influenced by Efb-C in CP/LP. Instead, they suggested Efb-C attacked complement intermediates that contain C3b. Therefore, in CP/LP, C3 convertase (C4b2a) was not affected by Efb but C5 convertase (C4b2aC3b) was inhibited, as evidenced by the decreased C5a production. Ehp was found to contain two C3d binding sites and showed higher levels of inhibition compared to Efb, though the mechanism of action was proposed to be similar. Nevertheless, the C3d fragment carries another important task: mediating interaction with complement receptor 2 (CR2) on B cells and facilitating B cell activation. Both Efb-C and Ehp were shown to completely inhibit C3d:CR2 interaction and its stimulatory effect on a B lymphoma cell line. The predicted binding site of CR2 on C3d was in close proximity to the residues that have been shown to be involved in Efb-C:C3d and Ehp:C3d binding. The exact competition mechanism remains to be confirmed . 1.4.3.3.3 Sbi Sbi is another secreted S. aureus protein that targets C3 activation. Sbi binds C3b but has a stronger affinity to C3dg. The binding was shown to be improved when the C3a domain was also present. These observations suggested the C3dg and C3a portion of C3 were important for Sbi/C3 interaction. By comparing binding profiles of different domains of Sbi, the C3 binding site was proposed to be located in its fourth domain (Sib IV). Interestingly, Sbi IV alone inhibited AP activation in a dose-dependent manner. However when the third domain was also present, incubation of human serum with this recombinant protein induced activation of complement, as shown by the degradation of native C3. A distinctive C3 derivative was present in Sbi-III-IV treated serum, whose molecular weight and migration behavior on two dimensional SDS-PAGE correspond to a transacylation product of C3b and Sbi. The cleavage of C3 activates an internal thioester moiety in the C3b fragment, which allows C3b to form cova lent bonds with hydroxyl groups in close proximity (e.g. bacterial surface). Thus it was proposed the Sbi III-IV provided a fluid-phase transacylation target for C3 cleavage and cause non-effective activation of the alternative pathway. Since mutational study confirmed the Sbi-IV was responsible for the complement inhibitiory effect, Sbi-III was proposed to be important in consumptive complement activation. Once again, Sbi IV adopts the triple helix structure, arranged in a similar fashion as Efb-c and Ehp (Fig. 1.2). Just like Efb and Ehp, the binding of C3dg to CR2 was inhibited by Sbi-III-IV, implying that Sbi may also influence adaptive immunity . 1.4.3.4 Preventing phagocyte extravasation and chemotaxis 1.4.3.4.1 CHIPS; FLIPr and FLIPr-like CHIPS (the chemotaxis inhibitory protein of S. aureus) was identified for its ability to prevent neutrophil chemotaxis to formylated peptide and C5a. CHIPS encodes a 121-amino acids (aa) secreted protein and presents in 62% of S. aureus clinical isolates. Postma et al demonstrated that CHIPS selectively and directly bound to C5a receptor (C5aR) and formylated peptide receptor (FPR) expressed on cell surface and competed with their respective ligands for binding. Receptor activation, as measured by the Ca2+ influx and murine neutrophil migration to the injury site, was inhibited. The two receptors were shown to interact with different areas on CHIPS. The N-terminal 6 residues of CHIPS, F1 and F3 in particular, were identified as the FPR binding sites. While the C5aR-binding domain was mapped to residues 31-121, which forms a packed structure similar to the ÃŽ ² grasp domain. Arginine 44 and lysine 95 were shown to be critical for its antagonizing activity. C5aR binds CHIPS through its N-terminus residues 10-18. These residues were suggested to be either involved directly in C5a binding or were required to stabilize the interaction. Therefore, CHIPS may function by direct competing with C5a or by disrupting the formation of the stable ligand/receptor complex . Two more S. aureus proteins were found to inhibit neutrophil chemotaxis. The secreted FPR-like 1 inhibitory protein (FLIPr) and its homologue FLIPr-like bound FPR and FPR-like 1 receptor (FPRL1). The N-terminal 6 residues of both proteins were important in both interactions but the phenylalanine was not critical for FRP binding. The inhibition of FPRL-1 by both proteins occurred in the nanomolar range. FLIPr-like was shown to be a potent inhibitor for FPR with activity comparable to CHIPS. However, animal infection models with chips or flipr isogenic deletion strains has not been reported. The contribution of CHIPS in bacterial infection is yet to be determined . 1.4.3.4.2 Map Map (MHC class II analog protein a.k.a. Eap) is a multifunctional 60-70 kDa secreted protein expressed by 97% of S. aureus isolates. It is an anti-inflammatory molecule that reduces leukocyte availability and function. Map can interact with a wide range of host ligands, including Fg, Fn and ICAM-1 (intercellular adhesion molecule-1). Map largely blocked ICAM-1 mediated firm adhesion and transmigration of neutrophil. In a peritonitis mice model, intraperitoneal injection of Map or pre-treatment of mice with Map showed 50-75% inhibition of neutrophil recruitment. Neutrophil infiltration in mice infected with a map- strain was 2-3 folds higher than that seen with a map+ strain, demonstrating Map inhibits ICAM-1 mediated neutrophil migration in vivo. Interaction of Map with ICAM-1 may modify signal transduction in leukocytes. NF-ÃŽ ºB activation and tissue factor release in THP-1 cells were diminished by Map treatment. A substantial amount of IL-6 and TNF-ÃŽ ± and a smaller amount of IL- 4 were released from Map treated human CD14+ PBMC in vitro. Anti-ICAM-1 antibody blocked the action, suggesting the induction was also mediated by ICAM-1. It is not clear if cellular processes other than cytokine production are also influenced, although Maps effect on PBMCs appears to be dose dependent . In addition to the cytokine changes, T cell function was impaired by Map. Mice treated with Map showed significantly reduced T cell mediated delayed-type hypersensitivity (DTH) and T cell proliferation. Adoptive transfer of T cells from Map-treated mice to untreated recipients prevented the recipients from developing DTH when challenged with allergen. The Map

Barney Vs. Sesame Street :: essays research papers

Barney Vs. Sesame Street Sesame Street and Barney The Dinosaur are two popular educational shows for children. Are they really teaching kids with the right techniques? Are they teaching kids anything at all? It's a battle to see which is better: Barney or Sesame Street. Sesame Street and Barney have totally different teaching techniques. Sesame Street captivates the audience with high joltage and fast scenes. The child barely understands what is going on and when they understand that scene, it's over and the next scene is almost done. The child does not learn well under these circumstances. Barney does not have the same JPM as Sesame Street but it still attracts the audiences' attention. The show is slower and more understandable than Sesame Street. Barney focuses on one topic for every show. The one that I watched, entitled "Up We Go", was about flying. You learn about kites, birds, planes and more. You get more out of the show than if it was about many topics like Sesame Street. The one we saw had many topics like eating healthy, dental hygiene, the airport and more. The child can have an overload of ideas for one day and get all mixed up. Both Barney and Sesame Street have songs in them. I found that Barney had many more songs than Sesame Street. The songs are used as jolts and they work well in getting the attention of the child. I found that the Barney songs were much catchier than the Sesame Street songs. They were slower, and other than the dancing, there was not much else happening. On Sesame Street, the background was changing, things were flying and colors were jumping. The attention was not put on the song by the kids, it was put on the actions on the screen. Barney, like Sesame Park, showed minimal biases regarding sex and race. The cast consisted of three boys and three girls. One boy was disabled but was as able as the other kids. The races on the show were mixed. They consisted of a Latino boy, a Chinese girl, an African-American girl and more. On Sesame Street there was less of a mix of races. They just had the primary races of the United States like African-Americans and Latinos. While watching Barney, I noticed that a main focus was imagination and

Politics and Religious Faith in the Media Essay -- Essays on Politics

Politics and Religious Faith in the Media On January 29, 3003, thousands of Americans were seated in front of their television screens, eagerly and somberly watching the man on the screen. During the man’s speech, the words â€Å"There’s power, wonder-working power† were brought forth, and it was those very words which have turned heads, and incurred opinions, articles, and editorials across the nation. Had this man been a preacher there is no doubt that his comments would have gone un-criticized. However, this man was not a preacher, but rather George Bush, the President of the United States of America. His comment did not escape notice nor criticism, and has become highlighted in the recent media focus on politics and religious faith. Just a week ago Newsweek published a cover story on â€Å"Bush and God†, and TIME magazine, USA Today, and The New York Times have all published articles and editorials concerning this topic. In response to the recent media coverage, Americans are sitting up as well, taking more careful notice, and often voicing their own opinions. As the journalists and newscaster are questioning to what extent personal beliefs are affecting political performance and agenda, I find myself questioning the journalists and newscasters themselves. How are they presenting this topic, and how are these presentations influencing the publics understanding of the truth of the situation? Is it possible to report on a topic as controversial and complex as religion and politics in such a way that is not biased or catered to popular opinion? Through my research I have found material to suggest that the media, specifically magazines, newspapers, and on-line articles, are not clearly delineating between tho se who favor Bush’s relig... ...nsorship.† Mass Politics: The Politics of Popular Culture. Ed. Daniel M. Shea. New York: Worth Publishers, Inc., 1999 Lampman, Jane. â€Å"New Scrutiny of role of religion in Bush’s policies.† The Christian Science Monitor 17 March 2003: A1+ Fineman, Howard. â€Å"Bush and God.† Newsweek 10 March 2003: 76-84. â€Å"Silent Evangelical Support of Bush’s Proposed War Against Iraq.† Morning Edition. Host Bob Edwards. Natl. Public Radio. WCAL, Northfield. 26 February, 2003. Religion in Politics. 19 & 20 March 2003. The Pew Forum on Religion and Public Life. http://pewforum.org/issues/display.php?IssueID=6. Gruener, Claude M. Letter. The New York Times. 14 March 2003 â€Å"Delivering the Good News.† MSNBC. Yourish, Karen. 19 March, 2003. http://www.msnbc.com/news/878520.asp Dr. Gary. Errant Skeptics. 19 March 2003. http://www.errantskeptics.org/Quotes_by_Presidents.htm

Free College Essays - Eliezer Wiesels Night :: Eliezer Wiesel Night Essays

Eliezer Wiesel's Night      Ã‚  Ã‚  Ã‚   The Book Night was the autobiography of Eliezer Wiesel.   This was a horrible and sobering tale of his life story.   The story takes place in Sighet, Translyvania.   It's the year 1941 and World War II is occurring. Eliezer was 12 at this time and wasn't really aware of what was occurring in the world concerning the Jewish people.   He had a friend who went by the name Moshe the Beadle.   Moshe was very good friend of Elezers'.      Ã‚  Ã‚  Ã‚   One day it was ordered that all foreign Jews in Sighet be deported by German troops.   They were told they had to wear yellow stars to identify themselves.   Eliezers friends Moshe was also a foreign Jew, which meant he had to be deported.   Eliezer did not see his friend Moshe for months.   When he finally saw him, Moshe was weeping.   Eliezer asked him what was wrong. Moshe told him he was in a concentration camp.   He said they threw him in a pit and shot his leg, but he managed to escape to worn him to flee for his life.   Eliezer didn't listen to him anyway.      Ã‚  Ã‚  Ã‚   About three days later, German troops entered Sighet.   They order the people of Sighet to surrender to them or die.   The people surrendered and had to give up all their possessions.   Moshe was right, it did happen.   All the people of Sighet were jammed into train cars and shipped to the concentration camp of Aushcwitz.   At that point Eliezer was separated from his family forever with the exception of his father.   There was a large crematory in Aushcwitz.   You could smell the burning flesh in the air. Eliezer was ordered to the crematory.   He came within two paces of it, but then was ordered to the barracks.   He was saved for that night only.   After that incident, he lived with fear of when was he going to die.      Ã‚  Ã‚  Ã‚   Eliezer later went to other concentration camps in Bakenau and Buna. During these years in the camps he lived through great suffering. Starvation, and survival.   He also witnesses thousands of people die and murdered including his own father.   Eliezer was finally shipped to Buchenwald.   Which would end up being his last stay at any concentration camp.   It was now the year 1945 and this ordeal was finally over.

Dozier a

1. Evaluate each of the different alternatives. Justify your assumptions and argue which is the best one for Dozier. After their bid was accepted, Dozier has three options to choose from. Of the three choices, the 1st alternative yields the most profit. However, the profit from alternative 1 cannot be guaranteed, and it is much more volatile. The company wants to expand its market to the U. K. and also guarantee the profit (while minimizing exchange risk). Therefore, alternative 2, which has a higher profit margin than alternative 3 is the best hedging choice for Dozier. Alternative 1Alternative 2 Alternative 3 Dollar value of the balance $1,505,086. 88 $ 1,501,438. 5 $1,493,995. 00 Dollar value of the contract $1,677,311. 33 $1,673,663. 00 $1,666,219. 73 Total cost $1,642,783. 00 $1,642,783. 00 $1,642,783. 00 Profit $34,528. 32 $30880 $ 23,437. 00 Percent of Profit 2. 10% 1. 88% 1. 43% Cost of Hedge N/A -1. 20% -1. 70% The detailed calculation is shown below. Alternative 1: Do Nothi ng Dozier would choose to remain unhedged, and expose itself to currency risk. We assume the company will exchange the 10% deposit into dollars and deposit into the U. S. anks directly. The company can obtain interest revenue from this part of deposit. The spot pound rate in U. S. dollars on January 14 is 1. 437. The company can get ? 117,500 ? 1. 437 = $168847. 5 when they exchange the deposit. Three-month deposits interest rate in the U. S. is 8% annually. Therefore, the interest rate would be 0. 08/4=2%. The company can get $168847. 5 ? 1. 02 = $172224. 5 from the 10% deposit. The company will receive GBP 1. 0575 million on April 14,1986. The exchange rate on April 14 remains unknown. However, the pound has weakened over the previous six weeks.CFO, Rothschild was also concerned that the value of the pound might depreciate even further during the next 90 days. We can set three possible rates with different possibilities. According to Exhibit 5, the 3-month forward rate is 1. 4198. This is the scenario that has the highest probability of occurring in the future because it is the most reasonable spot rate on April 14. This is the base case from which to measure the other two alternatives. We can also run the regression (see appendix, graph 1) on the recent eight weeks and get the exchange rate on April 14, as the worst case.Another regression can be run based on the half year exchange rate (see appendix, graph 2). This case can be set as the best one which shows long term data. Receivables Exchange Rate Revenue Probability Base Case ?1,057,500 1. 4198 $ 1,501,438. 50 50% Worst Case ?1,057,500 1. 3617 $1,439,997. 75 25% Best Case ?1,057,500 1. 4917 $1,577,472. 75 25% The total expected revenue from receivables would be: Base Case Revenue ? Probability + Worst Case Revenue ? Probability + Best Case Revenue ? Probability = 1,505,086. 88. Therefore, Revenue from Receivables $ 1,505,086. 88 Revenue from Deposit $172224. 45Total Expected Revenue $ 1,677,311. 33 Tota l Cost $1,642,783. 00 Profit $34,528. 32 Percentage of Profit 2. 10% We can also perform break-even analysis here. The exchange rate would be 1. 3906 when the profit is zero. Therefore, if the pound depreciate to 1. 3906, the company would suffer a loss for this contract. Alternative 2: If Dozier sells pounds forward 90 days Dozier would incur an obligation to deliver pounds 90 days from 1/14/86 at the rate of 1. 437. This would ensure that Dozier would receive a certain amount of money, regardless the change of exchange rate. The 3-Month Forward Rate in U. S.Dollars on 1/14/86 is 1. 4198 and the balance is GBP 1. 0575 million. Thus, Dozier would receive 1. 4198 ? ?1. 0575 million = $1501438. 5 after three months. As we discuss above, the company can get 168847. 5 ? 1. 02 = $172224. 5 dollars from the 10% deposit. Therefore, the actual revenue of the contract is 1501439 + 172224. 5 =$1673663. The total cost is $1642783. Thus the profit is 1673663 – 1642783 = $30880. The perce nt of profit is 30880/1642783 = 1. 88% If the rate remains the same as 1. 437, the rest pounds has the value of 1. 437 ? ?1. 0575 =1519627. 5 million. The cost of hedge is (1501438. 5 – 1519627. )/1519627. 5 = -1. 2% Alternative 3: If Dozier secures a 90-day pound loan Dozier can also do a spot hedge, which worked similarly in that it also created a pound obligation 90 days. Dozier would borrow pounds from bank and exchange the proceeds into dollars at the spot rate of 1. 4198. Dozier would use its pound receipts, ? 1. 0575 million, to repay the loan. The rate of loan would be at 1. 5% above the U. K. prime rate. Since the loan rate for three months is (1. 5% + 13. 5%)/4=3. 75%, Dozier could receive ? 1. 0575 million/ (1+3. 75%) = ? 1019277 on 1/14/86. Then he would exchange them to dollars.With the spot transaction at 1/14/86, Dozier would get ? 1019277 ? 1. 437 =$ 1464701. 2 on 1/14/86. To get more profit, Dozier would deposit dollars. At end of three months, they would rec eive $ 1464701. 2 ? (1+8%/4) = $1493995 for ? 1. 0575 million. As we discuss above, the company can get 168847. 5 ? 1. 02 = $172224. 5 dollars from the 10% deposit. Thus, the actual revenue of the contract is 1493995 + 172224. 5 =$1666219. 73. The total cost is $1642783. Ergo the profit is 1666219. 73 – 1642783 =$ 23437. The percent of profit is 23437/1642783 = 1. 43%. The cost of hedge is (1493995 – 1519627. 5 )/1519627. = -1. 7% 2. What is the relation between the forward rate,the spot rate and the interest rates in the US and the UK? Below are the formulas from the suggested reading. It can show the relationship between the forward rate,the spot rate and the interest rates. Forward rate in U. S. : Forward rate in U. K. : If we divide forward rate in U. S. by forward rate in U. K. , we can get formula below: Generally, the relationship between currency spot rates and futures rates are based on interest rate parity, in which the exchange rate is determined by the rela tive interest rates, and the expected future spot rate.From the formulas above, we can see that if the US risk-free rate is less than the British pound rate, the futures exchange rate will be less than the current spot exchange rate. Relative to the spot rate, the forward rate tells you whether interest rates in one currency are higher or lower than those in the other currency. The international Fisher effect suggests the currency of the country with the higher nominal interest rate is expected to depreciate against the currency of the country with the lower nominal interest rate, as higher nominal interest rates reflect an expectation of inflation. 3.Are there alternative ways for Dozier to protect itself from currency risk? Yes. There are five alternatives for Dozier to protect itself from currency risk. First, Dozier could offset the pound exchange risk by hedging with options. Calls would be used if the risk is an upward trend in price, while puts are used if the risk is a downw ard trend. If the risk was a depreciation of the pound, Dozier would need to buy put options on pounds. If pounds were to depreciate at the time Dozier receives its pound revenue, then Dozier would exercise its right and thereby effectively obtain a higher exchange rate.However, if the pound was to appreciate instead, Dozier would then let the contract expire and exchange its pounds in the spot market at the higher exchange rate. The options market allows traders to experience unlimited favorable movements while limiting losses. This feature is unique to options, unlike the forward or futures contracts where the trader has to forego favorable currency rate movements, plus there are also no limits to losses. The advantages of options over forwards and futures are the limited downside risk and the flexibility and variety of strategies made possible.Also, in options there is neither the initial margin nor the daily variation margin since the position is not marked to market. This relie ves traders from potential cash flow problems. Options are however, more expensive because they are much more flexible compared to forwards or futures. The option price is therefore its disadvantage. Another alternative for Dozier to protect itself from currency risk would be to use profits generated in British pounds to buy durable goods which are then sold in the US in dollars. For example, British beer.Presumably, the beer industry has a low beta since most people are going to drink, regardless of economic standings. There may even be a tendency for people to drink more during hard economic times. If Dozier were to purchase British beer in pounds, the value would be retained when resold in the US, thus protecting the firm from exchange risk. The primary cost associated with this may be tariffs and other taxes on imports to the U. S. Third, similar to the alternative above, Dozier could direct profits earned in British pounds into other U.K. investments. From the case, it is belie ved that the company wants to continue its international growth. The company can use the profits earned to expand the overseas market. Holding a large portfolio of international units can in the long run, reduce unsystematic risk isolated in the U. S. Fourth, because the pound might depreciate further during the next 90 days, Dozier can accelerate the completion of the project to offset currency risk (predicted depreciation of the pound) by collecting payment prior to the agreed upon date.Finally, the company can benefit from currency swap. It is a foreign-exchange agreement between two institutions to exchange aspects of a loan in one currency for equivalent aspects of an equal in net present value loan in another currency. Currency swaps are motivated by comparative advantage. For instance, if Dozier needed to acquire pounds and a U. K. company needed to acquire dollars, these two parties could arrange to swap currencies by establishing an interest rate, an agreed upon amount, and a maturity date.These currency swaps are negotiable for at least 10 years making them a very flexible method of foreign exchange. Additionally, since swaps are considered a foreign exchange transaction, they are not required to be listed on a firm’s balance sheet. 4. Should Dozier diversify its currency risk? Does it have a comparative advantage in remaining unhedged? Yes, controlling the currency risk is an important instrument for controlling and improving performance of international investments. In remaining unhedged Dozier may not necessarily have an advantage.While option 1 was calculated to be the most profitable, this depends on the exchange rates remaining relatively high. The exchange rates will fluctuate. The value of the dollar could increase or the pound could decrease leading to losses. If it goes below 1. 3906, the company would suffer a loss. It is the first time that Dozier is expanding into a foreign country. For Dozier to continue to expand into foreign ma rkets, it is essential that cash flows are generated. Hedging offers Dozier exchange rate risk protection in the vent the value of the British pound falls. It would eliminate the risk and guarantee the necessary cash flows. For the same reasons however, it may be Dozier’s best interest to remain unhedged. If they already planned for a 6% profit margin, exposing themselves to more risk may be the only way to get a this return. A riskier, unhedged position may be further incentivised by a principal agent problem between Rothschild and the CEO. It is not explicitly stated, but as the CFO, Rothschild’s job may be on the line if he does not perform.Therefore, the added risk in order to cover for past 6 week’s exchange losses may be his last hope. It will not cost him any more to take on the additional risk if he is already facing a high probability of losing his job. Agency costs aside, the question boils down to this: Is a high probability of a small profit better t han a small probability of a big profit. Considering this is their first international project, it might be best to go with what is certain, taking small steps, and learn from their mistakes going forward into future projects. Appendix Graph 1 Graph 2