Research Proposal Paper Example | Topics and Well Written Essays - 1750 words

Paper - Research Proposal Example The understudies will be asked to finish an overview (Drummond,2014). The finished study will create the greater part of the essential parts to position every understudy in the right area of the 3 X 3 factorial outlines. The study will contain an assortment of inquiries identified with the theory of this study to focus the examples. They are between the utilization designs/ recurrence of the utilization of video games with the kind of video diversion to the understudies achievement and psychological state. The overview will likewise educate with respect to the additional curricular exercises of the understudies since this kind of out of school association might likewise relate to higher or lower government sanctioned test scores. This study is critical due to how essential state-administered testing has ended up, and the amount time and cash get put into enhancing the scores of understudies here. Technology is an apparatus that educators can use to help adapting, yet brain research tutoring must be first. In the event that instructors and therapists do not see how to help learning, engineering utilization will be ineffectual and wasteful. The key determinant of our prosperity and enthusiastic dependability will not be the quantity of machines obtained or links introduced. Instead, it is how people characterize instructive dreams, plan and help staff, outline educational program, location issues of value, and react to the quickly evolving world. Innovation gets utilized as a part of different courses than for instructive profits. Engineering got additionally created for amusement and relaxation. Video games are a type of engineering incorporating visual, sound-related, and kinesthetic/material reenactment structures. Not all, yet numerous understudies are excited in the use of video games in the timetable of relaxation time and unwinding. Video games have advanced a long ways past the

Law dis6 Essay Example | Topics and Well Written Essays - 250 words

Law dis6 - Essay Example It is these decisions that lead to success or failure of the business hence its ability to offset the loan. The organization structure is therefore an important factor to consider when deciding about the loan. A Pre-bureaucratic structure would be best as the business is medium-sized, requires limited specialization and the structures allows for quicker decisions which are imperative in a restaurant business. How realistic and achievable the business plan is, the borrowing history of the partners, the values of the collateral provided by the partners, the ability of the partners to offset the loan in the period provided should the business fail and the ability of the guarantors, if any, to offset the loan should the partners fail to do so. The nature of the business would make a considerable difference. In a franchise, there are less teething problems as the brand name is already established. The business model is already tested as the franchisor is successful. However on the considerations, one must appreciate that the decision making of the entrepreneurs is limited as the franchisor has a significant say in the operation of the business hence their growth may be limited to a certain level. The amount of fees to be paid to the franchisor as royalty as well as what the franchisee is to pay as training and advisory fees. The fees should not be too large as to hinder leave too little money for the daily operations of the business. Another factor to consider is the role in decision making of the franchisor which should not be too large and the duration of time that the franchise is supposed to take place. The creditor ought also to consider the business format- whether trade name franchising or business format franchising The Franchise Disclosure Document (FDD) which should be made available to the franchisee by the franchisor, two weeks before payment of any fees. The document contains

The Knowledge of Human Existence Essay Example for Free

The Knowledge of Human Existence Essay Movies provide the audience with a unique experience. Not only do they entertain, they allow the audience to explore their own preconceptions. The most vital preconception that movies allow the viewer to explore and interact with is the definition and formation of knowledge. For centuries man has grasped for the true definition of knowledge. In this struggle many have fought for a unifying definition, this great conflagration of discourse and study did not lead to a unified definition of knowledge. Moreover, it leads to the question that still beats in the hearts of the philosopher and the movie-goer. What can human beings know about the experience of existence? How do we define it? Man’s struggle with the definition of knowledge and how we define existence is a driving force behind the questions asked by philosophers throughout history. From Plato to Descartes, from Aristotle to Kant, the understanding of existence became nearly an obsession of the great philosophical minds. It is this â€Å"obsession† that drives Hugh Jackman’s character, Robert Angier in Christopher Nolan’s The Prestige. In this â€Å"obsession† Angier finds his match with Keanu Reeves’ character, Neo in Andy and Larry Wachowski’s The Matrix, whose transformation from computer hacker to an almost God like position of knowledge, stems from his obsession with defining his existence. While it is the character Neo who is lead or rises to a position where it is possible to fathom the nature of existence, it is the audience whom Christopher Nolan guides to this level in The Prestige. Before an understanding of existence can be examined, it is important to define the role of the audience in Nolan’s The Prestige. While Nolan’s characters are subject to an â€Å"obsession† directed towards the knowledge of each other’s methods, the true character receiving knowledge is the viewer. Cristel Russell in a piece titled, â€Å"Rethinking Television Audience Measures: An Exploration into the Construct of Audience Connectedness,† written for Marketing Letters in 1999 discusses the degrees of connection a television audience has. While Russell’s piece is intentioned for an understanding of the relationship between a television audience and the images on screen in the sense of how to market to the audience, the similarity of the mediums allow for this to be an example for the filmic experience as well. Russell’s study asserts the strength of the connection the audience has, â€Å"viewers often reported that they imitate some of the intangible aspects of their television show, from the lifestyle of the actors to the philosophy portrayed by the character,† (Russell, 1999, p. 401). Russell chooses the word â€Å"their† to suggest a possessive, included, position that the viewer takes with the images portrayed on the screen. It this suggestion of inclusiveness that suggests that the viewer becomes part of â€Å"their,† show. No longer is the viewer simply an audience member; they are a part of the cast chosen by the director and as such they become a necessary medium for explication of â€Å"philosophy† as is suggested by Russell. Nolan’s audience is not simply viewing, they are interacting with the film, and as such they are guided by Nolan to a realization, just as Robert Angier is. While, Angier’s â€Å"obsession† for knowledge is limited by his insatiable desire for revenge, he ascends on a philosophical scale. While this may seem reminiscent of the story of Plato’s cave, where a man trapped is freed by realization that his existence is limited to projections on the wall of his cave, Plato’s example does not serve Angier. It isn’t until his death at the hands of his old enemy that Angier is able to transcend to the realm of knowledge necessary to understand existence. It is in this moment that he realizes that all the tangible evidence of how his rival’s tricks were performed, were not the true illusion. The truth that Angier in his final moments is lead to believe, is that sacrifice is a necessity for perception to become actual existence. In his dying moments Angiers defines his own understanding of his purpose, while the film-maker paints it in a romantic sense, it provides the viewer with the true understanding of individual existence. It is just that. Individual. While shaped by the collective experience, the only thing a human being can say for certain is that their existence is their own, folding too completely into an empirical collective experience is as unfulfilling as life without death. Hence, Angier must die by the end of the film. (Nolan, 2006). Knowledge cannot be limited solely to a scientific explanation of why things are and why things aren’t. John Cottingham’s piece, â€Å"The Question,† from The Meaning of Life provides the seeker of knowledge with an explanation for the limitedness of scientific inquiry. In the piece Cottingham highlights â€Å"religious discourse† throughout time as necessary force for further investigation into the why that creates the human need for knowledge of existence. While â€Å"religious discourse† may not provide an exact answer to what existence is, this is inconsequential as according to Cottingham, â€Å"But its advocates would urge that it none the less assuages the nausea, the ‘nausea’ as Jean-Paul Sartre called it, that we feel in confronting the blank mystery of existence,† (Cottingham, 2003, p. 9). Here Cottingham’s inclusion of â€Å"religious discourse† as essential in understanding the â€Å"blank mystery of existence,† seems to undermine a definition of existence based entirely on science. â€Å"Science† as discussed in Cottingham’s discourse should be understood as empirical knowledge. Based upon Cottingham, this empirical knowledge, the tangible is limited in its ability to assist human beings in their understandings of existence. It is into this gladiatorial arena where Rene Descartes jumps as a opponent of a solely empirical understanding of existence. Rene Descartes provides a rational approach to the problem of understanding existence. Descartes rationalism is based upon his definition of the â€Å"material† of existence. Rather than being bogged down in the definition of â€Å"material,† Descartes comes to the conclusion that, â€Å"Consciousness is the essential property of mind substance,† (Collinson, 2006, p.81). Descartes’ definition of the â€Å"essential property† as espoused in Diane Collinson’s Fifty Major Philosophers opens the door for how human existence is defined. The â€Å"essential property† of existence is not based on tangible experience. Collinson highlights Descartes suggestion that the mind experiences the empirical sense of the body, but not because of direct physical experience, rather that, â€Å"ideas of primary qualities are not derived from sense experience but are innate,† (Collinson, 2006, p 83. ). This idea of â€Å"primary qualities† can be applied to the question of existence as experienced by Neo in The Matrix. Neo’s character ascends from a plateau of empirical existence in the beginning of the film. He does not know that he is actually being deceived, that his definition of existence is a computer created dream state. This dream state although realized to be a manifestation of a computer program, is seen by Neo in his earliest iteration as real. He does not know he lives within a deception, because the computer-generated Matrix  maintains all the â€Å"essential qualities† of existence in Neo’s mind. It is not until he meets Morpheus that what he considers existence is a facade. While he maintained a certain amount of skepticism, Neo’s first iteration as Thomas Anderson does not suffer to greatly from the problems that Descartes mused about in the sense of â€Å"dualism. † Neo before meeting Morpheus is happy to accept his existence just as it is because without the outside of influence of Morpheus’ experience, the Matrix holds up to the ideal of the innate nature of existence. Similarly, the audience of The Prestige is like Neo. They are lead astray from the true realization of existence, in particular the truths revealed at the end of the movie, by Nolan. The audience does not know that there is a form of deception taking place. Sure, there is the acknowledgement that the other characters practice in deception, but as the audience is intertwined into the film as an additional character, they are unable to see the greater deception at play. Like Neo, the viewers of The Prestige must go through further iterations in order to understand that while seemingly â€Å"innate† in the sense of Descartes, that the existence portrayed is not the truth. In both cases, an outside influence contends against the assumed support of the rationalism proposed by Descartes. As Neo is awakened into the real world by Morpheus, he ascends another rung on the ladder to an identifiable definition of what composes existence. As Morpheus instructs Neo in the realities of the computer dominated manifestation he had accepted as existence, he is in fact reflecting what Kenneth Westphal refers to as, â€Å"the Humean objection, that the appearance of physical objects in space and time is a deceptive illusion produced by our imagination,† (Westphal, 2006, p. 781). In this direct reference to David Hume In his piece,† How Does Kant Prove That We Perceive, And Not Merely Imagine, Physical Objects,† written for Review of Metaphysics, Westphal endorses Morpheus’ claim to Neo that his imagined self when inside the Matrix is just as real as Neo in the real world. If Neo dies in the Matrix, even-though his computer generated image is simply a construction of the mind, he also dies outside of the Matrix. The creation of two distinct images of the same person, with equal mortality seems to suggest a dichotomy, that deception and perception are interchangeable. That the tangible and the imagined are one and the same when it comes to defining existence, but this understanding is only reached by a communal understanding of existence. Neo was perfectly fine with accepting his previous understanding of the world and his violent initial reaction to Morpheus’ suggestion, points to this. This notion rather than serving to clarify how existence is determined actually muddles the idea. It almost works to endorse a sense of self-deception. (Wachowski, 1999). The concept of self-deception and the reality of the imagined is examined by through the audience’s viewing of the truth behind Angier’s final downfall in The Prestige Angier buys into the imagined and as a result must be destroyed. The final scenes of the film refer the audience, now so deeply involved in the deception to the introduction by the character, Cutter, â€Å"Now youre looking for the secret but you wont find it, because of course youre not really looking. You dont really want to know. You want to be fooled,† (Nolan, 2006). This suggestion that the viewer doesn’t â€Å"really want to know,† explains the downfall of Angier. He was so hopeless caught up in his desire for revenge that he limited his imagination, he only placed importance on the empirical evidence, that his enemy had been hung. He allowed himself to be deceived. Similarly, the character Cypher in The Matrix, desires to allow himself to be deceived. Rather than endorsing an empirical knowledge of existence in this desire, this â€Å"obsession,† it does quite the opposite. Both Cypher’s desire and Angier’s downfall in contrast to the admirable outcome favored upon Christian Bale’s character, Alfred Borden, endorse the idea that deception is as real as existence. The ability to choose between to two, between the intangible, (elucidated here as deception) and the tangible is the defining notion of human existence. This seems to reinforce a Kantian understanding of existence. Kant’s definition of the human experience while seemingly based in sensory information and in that regard would be subject to the same deceptions of the senses that plagued Rene Descartes. However, Kant’s argument trumps this understanding. Diane Collinson brings forth Kant’s understanding of experience and existence, â€Å"Things-inthemselves cannot be known ‘even if we could bring our intuition to the highest degree of clearness’. They are the non-sensible causes of what we intuit,† (Collinson, 2006, p. 123). Kant’s theory on knowledge, at least in part, suggests that although senses provide humans with a lens to view the world, that this is limited because in truth the perceived â€Å"cannot be known† no matter what level of ascendency the viewer reaches. This first portion of Kant’s definition of the knowledge of human experience is reflected in the downfalls of both Neo and Robert Angier. Both must fall in order to support this theory, but in falling they are able to transcend and realize that they were unable to fathom their experiences. Angier had to have his rival’s mystery elucidated for him. Neo had to die in order to reach a position similar to that of a demi-god where he was no longer limited by the human existence. The agents in The Matrix repeatedly call attention to this by discussing the weak and vileness of the humans they have enslaved. In order to transcend to this level of knowing both characters had to fail. They had to realize that experience and existence cannot be known simply from the sensory or the perception. It requires sacrifice, but the knowledge that comes out of the sacrifice is limited to the individual. Immanuel Kant endorses this assertion of the individual in existence. Moreover it Is in his acceptance of the individual’s lack of ability to discern between perception and the empirical Kant provides an argument against the aforementioned â€Å"Humean objection. † Whereas Hume argued that the knowledge of the physical is a deception produced by the imaginative capacities of the human mind, Kant dispelled this conjecture of Hume’s. This facet of Kantian idealism is reflected in his next contention against the Humean, â€Å"but Kant regarded Hume’s strategy as inadequate since it left the causal principle without any justification. His own account establishes a third class of propositions, one whose propositions, like those stating matters of fact, tell us something about the world and are synthetic rather than analytic but which are also necessary in that they have an a priori element, that is, an element that is not derived from sense perception,† (Collinson, 2006, p. 124). Collinson highlights Kant’s transcendence of Descartes’ and Hume’s positioning of sense perception. By allowing for â€Å"synthetic† propositions or ideas about the world, including that of human existence, Kant opens up a window to air out the farce that perception and the empirical are the measures by which existence is judged. Existence in this sense being â€Å"synthetic† is entirely based upon the individual. The individual, although knowledgeable of the deceptive nature of perceptions can choose to limit their knowledge of existence to those perceptions, as did Robert Angier. Or the individual can create their â€Å"own† synthetic perception of the world, if they understand that they cannot fully understand existence. Both characters ascend the scale of knowledge, but in order to truly understand the purpose of existence, they must fall. It is in this final fall, that both are allowed to finally acknowledge, to finally understand, the truth of their existence. In both movies, the characters, including the character of the audience in The Prestige, are guided to make a choice. The implications of this choice while not entirely revealed to the character upon deciding, reflect their decision to define their own existence. The character just like the human being, chooses what to make of their existence in whatever time and place they reside. It is not a communal definition of existence or an all-encompassing one. The knowledge of what existence is limited solely to the individual. Works Cited Collinson, Diane and Plant, Kathryn. â€Å"Emmanuel Kant (1724-1804). † Fifty Major Philosphers Routledge, 2006, pp. 121-127. Collinson, Diane and Kathryn Plant. â€Å"Rene Descartes (1591-1651),† Fifty Major Philosopher, Routledge, 2006, pp. 79-84. Cottingham, John. â€Å"The Question,† On Meaning of Life, Routledge, 2006, pp. 1-31. Nolan, Christopher (Producer), Nolan, Christopher (Director). (2006). The Prestige [Motion Picture]. United States: Touchstone Pictures. Russell, Cristel Antonia and Puto, Christopher. (Nov 1999). â€Å"Rethinking Television Audience Measures: An Exploration into the Construct of Audience Connectedness. † Marketing Letters 18 (4). Retrieved from: http://www. jstor. org. ezproxy2. lib. depaul. edu/stablett Silver, Joel (Producer), Wachowski, Andy and Larry (Director). (1999). The Matrix [Motion Picture]. United States: Warner Brothers. Westphal, K. R. (2006). HOW DOES KANT PROVE THAT WE PERCEIVE, AND NOT MERELY IMAGINE, PHYSICAL OBJECTS?. Review Of Metaphysics, 59(4), 781-806. Retrieved from: http://web. ebscohost. com. ezproxy2. lib. depaul. edu.

Rheumatoid Arthritis Treatment Methods

Rheumatoid Arthritis Treatment Methods INTRODUCTION Autoimmunity is the inability of an organism in recognizing its own parts as  self, which triggers an abnormal immune response against its own cells or tissues. Due to such a response, autoimmune diseases occur. Autoimmune diseases are broadly divided into the following: Systemic autoimmune diseases: The symptoms and damage occurs throughout the body, i.e the antigen is not tissue-specific. Localized autoimmune diseases: The damage is localized, i.e., the antigen is tissue specific. Rheumatoid arthritis (RA) is a chronic  inflammatory, systemic autoimmune disorderthat may affect many tissues and organs, but mainly attacks the flexible (synovial) joints. 75% of the reported cases of RA occur in women, especially at age: 30 and 40 years and between 50 and 60 years (Bach, 1982). It can be a disabling and  painful  condition, which can lead to consequential loss of mobility and function if not treated adequately. But it is still unclear whether T-cells primarily respond to a microbial antigen, or a self-constituent antigen (Chiniet al., 2002). Lesions developed in RA appear to be involved in both cell-mediated and humoral responses. Prior research work focused on identifying the cells present in the affected synovium, and has been concluded that CD4+ T lymphocytes, active B lymphocytes, and plasma cells, combined with well-formed lymphoid follicles having germinal centers (in more serious cases), are present in the synovium of the patients (Abbas et al., 1994). Major cells present in the synovial filtrate of patients are T-cells, and a partial therapeutic effect was observed due to depletion of T-cells in these patients (Berneret al., 2000). Present understanding of RA conveys that TH1 cells which are specific for a particular antigen (which hasn’t been identified yet) are present in the joints of the patients. Pathogenesis and symptoms Fig1.1: Release of cytokines due to T-cell activation causing an inflamed synovium and pannus. Cytokines released in the synovium are Interleukin(IL)-1, IL-8, Interferon-gamma (INF-gamma), and Tumour Necrosis Factor-alpha(TNF-alpha). But the clinically important ones are IL-1 and TNF-alpha. These cytokines stimulate increase in collaginases, IL-6, chemokines, nitric oxide and Cyclo-oxigenase-2(COX-2) production. The combined action of these and a few others like IL-2 and IL-4 lead to the pathogenesis of the disease. Other than antigens, RA also involves antibodies- this is most likely due to formation of immune complexes. The auto-antibodies produced are called ‘rheumatoid factors’ and are specific to the Fc region of IgG. This rheumatoid factor is an IgM antibody and hence the immune complex consists of IgG-IgM which cause the damage (Janeway et al., 2001). Symptoms include stiffness, pain, swelling, and erythema, joints become tender, swollen, and warm. As it progresses, multiple joints would be affected (polyarthritis). The clinical manifestations are collection of polymorphonuclear leukocytes and macrophages at the inflamed region, cartilage damage, and, destruction of the joint Synovitis (inflammation of the synovium) can lead to  tethering  of tissue, lack of movement and erosion of the surface leading to deformity and loss of function. Systemic complexities are damage to various other organs like lungs, myocardia, pericardia pleura, eyes, and Central Nervous System as a result of inflammatory reactions (fig-1.1). Many agents are now available to treat RA, and many of them are monoclonal antibodies. Several new monoclonal antibodies are currently under development and hopefully will be available as other alternatives The focus of this paper is to state the latest therapeutic monoclonal antibodies being used for RA treatment, to state their merits and demerits and whether they are better than normal drugs/medication. Monoclonal antibodies with different mechanisms of action and route of administration are discussed and whether they pose as good therapeutic agents with an acceptable safety profile. 2. REVIEW OF LITERATURE 2.1  Treatment of Rhematoid Arthritis Some of the treatments for RA are: Anti-TNF-alphaTreatments Medications Therapeutic monoclonal antibody treatment Earlier it was believed that if one cytokine signal cascade was blocked then another cytokine would takeover. It was hypothesized that IL-1 caused the cartilage and bone damage.Through a study(at Kennedy Institute of Rheumatology), it was found that IL-1 bioactivity had stopped due to TNF-alpha blocking. This led to the development of anti-TNF-alpha treatments like- cyotokine antibodies and soluble-receptor antagonists (Feldmann et al., 1999). There are mainly four types of medications being used- Disease-modifying anti-rheumatic drugs (DMARDs), Non-steroidal anti-inflammatory drugs (NSAIDs), immuno-suppressants, and corticosteroids (glucocorticoids).(Rang et al.,1995). DMARDs include pencillamines (Cuprimine ®, Depen ®), gold compounds (Myochrysine ®, Ridaura ®) and chloroquine (Plaquenil ®). Although their mechanism of action is not properly understood, they have a very significant effect on RA patients. NSAIDs like asprin, ibuprofen (Advil  ®), ketoprofen (Orudis ®), naproxen (Naprosyn ®), etc.. have a variety of effects like anti-inflammatory, anti-pyretic, and analgesic effects.Immuno-suppressants like cyclosporine and cytotoxic agents like azathioprine suppress both humoral and cell-mediated immunity. Corticosteroids like prednisone, hydrocortisone, etc., have immunosuppressive and anti-inflammatory effects (Rang et al.,1995). 2.1.1 Therapeutic monoclonal antibodies: Each B-cell synthesizes only one kind of antibody and every organism has various populations of B-cells which secrete various antibodies specific to various antigens being recognized. But in order to turn this function into a helpful tool, we need huge amounts of a same antibody. So we need to culture a B-cell population originating from the same ancestral B-cell and hence obtaining the same kind of antibodies.Such a population of cells are called ‘monoclonal’ and the antibodies are‘monoclonal antibodies’(mAbs).Such monoclonal antibodies used for various therapeutic purposes are referred to as ‘therapeutic monoclonal antibodies’. If a specific antibody of a B-lymphocyte is needed, that B-cell should be secreted in an organism. So the antigen for which the antibody is needed is injected into a mouse and it secretes the B-cell antibodies against the antigen. Such B-cells are isolated from the spleen and fused with myeloma cells (using Poly Ethylene glycol, or electroporation), forming hybridomas. To selectively isolate the hybridoma cells, they are grown in HAT(Hypoxanthine AminopterinThyamidine) medium. (Fig 2.1.1) The cancer cells are HGPRT- and the B-cells are HGPRT+(HGPRT is an enzyme Hypoxanthine-guanine phosphoribosyltransferase which helps in the synthesis of nucleotides from hypoxanthine). Therefore, all the unfused myeloma cells die in the HAT medium and all the unfused B-cells can’t divide for long and only the hybridoma cells survive indefinitely. It is from these cells that the antigen-specific antibodies are labelled and isolated using radioactivity or immunofluorescence. Fig 2.1.1- A summary of the process of monoclonal antibody production. Types Till date there are four types of therapeutic mAbs- Murine Chimeric Humanized Human Murine antibodies (suffix omab)refer tomAbs made from any mammal of the family muridae (like mouse, rat). These mAbs were produced using hybridoma technology and were analogous to murine antibodies. But these were not a success because immune complexes formed due to which they only had a short half-life in vivo and caused cytotoxicity resulting in allergies and anaphylactic shocks .Hence these were replaced by chimeric and humanizedmAbs.Chimeric mAbs (suffix ximab) has variable regions of murine and constant region of humans fused together (they are 65% human). This decreases immunogenicity. Humanized antibodies (suffix –zumab) are made by grafting murine hyper-variable region onto the amino acid region of the human Abs (they are 85% human). However, these antibodies lacked the specificity of their parent murine mAbsso, affinity was increased by introducing mutations in the CDR (complementarity determining region). Phage display libraries or transgenic mice are use to produce human mAbs (suffix –umab). In this the murine genome is injected with the human immunoglobulin genes due to which it becomes transgenic. This mouse is injected with the desired antigen to yield the subsequent mAbs(Hudson PJ, Souriau C., 2003). 2.1.1.1 Monoclonal Antibodies Directed Against TNF-ÃŽ ± TNF-ÃŽ ± is a key mediator of the inflammation-induced joint damage that is a hallmark of this disease. Monoclonal antibodies to TNF bind soluble and transmembrane TNF, thereby down-regulating TNF-induced immune responses including adhesion molecule expression, cytokine production, matrix metalloproteinase production, neutrophil activities, dendritic cell function and osteoclast differentiaion. (Blumi S, Jet al.,2012) Monoclonal antibodies to TNF, except for certolizumab have the ability to lyse TNF-expressing cells in the presence of complement. (Kukar M, et al.,2009). Currently there are four mAbs approved for the treatment of RA Infliximab This is a chimeric IgG1 mAb and has human constant region with murine variable regions.(Perdriger A., 2009). This is best used with methotextrate(MTX) and is available only in the intravenus form. In 2001, it was approved by the FDA in combination with MTX to treat moderate to severe RA. Effectiveness and improvement in the disease compared to placebo was shown in multiple, randomized trials(Elliott MJ, et al., 1993) ,( Lipsky PE, et al., 2000), (MainiRN, et al., 2004). It was proven to be effective in early stages of the disease (et al., 2004).Given that influximab is comprised of a significant proportion of murine protein it was anticipated that patients would develop antichimeric antibodies that could impair the efficacy and increase the risk of infusion reactions. The combination of infliximab and MTX results in a substantial reduction in antichimeric antibody and increased serum infliximab levels.. Adalimumab Adalimumab is a human recombinant IgG1 mAb that has no murine component and is produced by phage display technology. It was FDA/EMA approved in, or soon after, 2002 for the treatment of moderate-to-severe RA as monotherapy or in combination with disease-modifying antirheumatic drugs (DMARDs). It is available in the subcutaneous form at a dose of 40 mg every 2 weeks. Despite adalimumab being a fully human antibody, anti-adalimumab antibodies have been detected in a significant number of patients(Vincent FB, Morland EF, Murphy Ket al.2013). Adalimumab responses and long-term sustainability may be reduced by anti-adalimumab antibodies, but adalimumab generally has good sustainability similar to that of etanercept and generally better than infliximab. Golimumab Golimumab is a fully human IgG1 anti-TNF-ÃŽ ± antibody that was generated and affinity matured in an in vivo system. It is very similar in structure to infliximab without the mouse protein. It was approved by the FDA/EMA in or soon after 2009 for the treatment of moderate-to-severe RA in combination with MTX(Kremer J, et al,2010). Certolizumab Certolizumabpegol is a humanized Fab fragment (Fc free) fused to a 40-kd polyethylene glycol (PEG) moiety. It was FDA/EMA approved in 2009 for the treatment of moderate-to-severe RA as monotherapy or in combination with MTX. It is available in the subcutaneous form at a dose of 400 mg at 0, 2 and 4 weeks, then every 2 weeks or 400 mg every 4 weeks. 2.1.1.2 Antibodies against B Cells B cells are critical to the pathogenesis of RA. Mature B cells may evolve into antibody producing plasma cells. Although the precise role of B-cell-producing autoantibodies in RA remains unclear, B cell and plasma cell infiltration into synovium has consistently been found.In addition to their role as precursors to antibody producing plasma cells, B cells may function as antigen-presenting cells and may also produce inflammatory cytokines and co-stimulatory molecules important for T-cell function.(TngYKO,et al., 2007). Rituximab As rituximab is a B-cell-depleting agent, chimeric/IgG1 monoclonal antibody which binds to the CD20 cell surface marker found on several maturation stages of B lymphocytes. It gained FDA/EMA approval in 2006 for the treatment of moderate-to-severe RA in combination with MTX in patients with inadequate response to anti-TNF. Rituximab is given via the intravenous route at a dose of 1000 mg for two doses 2 weeks apart for each cycle. The first study evaluated rituximab in RA was reported by Edwardset al., 2004.Four treatment groups consisting of MTX monotherapy, rituximab monotherapy, rituximab plus cyclophosphamide and rituximab plus MTX were compared, and all rituximab groups had a better ACR20 response compared with MTX monotherapy, with a comparable safety profile. 2.1.1.3 Antibodies That Interfere With IL-6 Function IL-6 is a cytokine produced by immunologically important cells that has an important role in T-cell activation and immunoglobulin secretion.It also stimulates synovial fibroblast differentiation and osteoclast activation.Dysregulation of IL-6 is also, in part, responsible for many of the generalized systemic effects of RA, including anemia of chronic disease as well as the acute phase reactants seen in this disease(Tanaka.Tet al. , 2010). Tocilizumab Previously called MRA, tocilizumab is a humanized/IgG1 mAb directed against IL-6 receptor in its soluble and transmembrane form. It was approved by the FDA/EMA in early 2010, or slightly before, for the treatment of moderate-to-severe RA in patients with an inadequate response to DMARDs and/or anti-TNF. A subcutaneous form of tocilizumab is currently under study. It is also indicated in patients with anemia of chronic disease since it dramatically increases hemoglobin as a consequence of reduction in hepcidin – the protein that inhibits iron utilization in RA. 2.1.1.4 Antibodies That Interfere With IL-1 Function IL-1 is produced by many cell types in response to myriad inflammatory stimuli and mediates multiple immunologic and inflammatory pathways. In patients with RA, the levels of naturally produced IL-1 receptor antagonist in the synovium is thought to be insufficient to counteract the increased levels of IL-1 produced in this disease (Arend WP., 2002) Anakinra Anakinra is the recombinant form of a human receptor antagonist (IL-1ra), and was approved by the FDA/EMA in, or slightly after, 2002 at a daily dose of 100 mg subcutaneously for moderate-to-severe RA that has been unresponsive to initial disease DMARD therapy. It has been studied in RA in several trials. (Fleischmann RM.et al,  2003) 2.1.1.5 Safety Infections Infections are the most common adverse event associated with the use of all biologics. Infection risks with anakinra and tocilizumab are probably similar to the TNF inhibitors, with rituximab perhaps having slightly less risk.Infection risk may be higher with the use of increased doses of infliximab and anakinra.Respiratory tract infections are most commonly reported. The risk of granulomatous infections, such as tuberculosis, is also increased in patients using monoclonal antibody TNF inhibitors. Malignancies The use of TNF inhibitors in patients with RA has not been associated with an increased risk of solid cancers, with the exception of cutaneous malignancies.. Malignancies have been reported with anakinra, tocilizumab and rituximab, but the risk does not seem higher than predicted in RA patients.(Ding T et al., 2010)Longer-term follow-up is required to more clearly understand the risk of malignancies with these drugs. Demyelinating diseases Symptoms of demyelinating neurologic dysfunction have been associated with TNF inhibitors. Resolution of these symptoms with drug withdrawal is common. TNF inhibitors should be withdrawn immediately if neurologic symptoms occur with use, and probably should be avoided in patients with pre-existing demylelinating symptoms(Ding T, Ledinghamet al., 2010).   3. DISCUSSION AND CONCLUSION 3.1 Drugs vs mAbs Just as monoclonal antibodies have various side effects the medication used for RA also have various complications There have been many news reports about how pain-killing drugs known as COX-2 blockers increase heart attack and stroke risks. Additional studies suggested that older non- steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen could also elevate heart risks.One of the culprits: methotrexate. It’s the most commonly prescribed disease-modifying anti-rheumatic drug, orDMARD, for rheumatoid arthritis. It’s also responsible for hair loss in about 1 to 3 percent of people. The hair loss happens because methotrexate is doing what it’s supposed to do – stop cells from growing, including cells causing inflammation and, unfortunately, hair follicles. Folic acid, which is commonly prescribed with methotrexate to mitigate some of its side effects, is a synthetic form of folate, a B-complex vitamin. It can help keep hair healthy, but it has not been fou nd to promote hair growth.Generally as a drug-related side effect, the hair loss is not drastic and the hair does not fall out in patches. And it usually grows back once the patients stop taking the drug.So as of now, most of thesuccesful treatments for RA using monoclonal antibodies are in combination with methotrexate. 3.2 Conclusion and future prospects Monoclonal antibodies with different mechanisms of action and route of administration are highly effective therapeutic agents in the treatment of RA with an acceptable safety profile. Choosing the appropriate treatment is a complex decision that is affected by clinical data, physician and patient preference, and payers. Almost undoubtedly, these types of agents will continue to be important agents in the rheumatologists armamentarium. How to use these agents more selectively, particularly regarding which agents are best for which patients, hopefully will be better established in the future with new biomarkers. Prediction as to what agent to use in the right patient at the right time is clearly a research priority. Monoclonal antibodies as new agents are expensive, and the cost/benefit analysis justifying their use is also critical to practitioners. . Many aspects regarding the efficacy and safety of the supposedly cheaper biologics need to be evaluated before they are available for w idespread use, but their availability and the emergence of new agents in the future may substantially change the RA treatment landscape. Although current therapies can reduce the signs and symptoms of RA for many patients, the quest for a cure (or a more complete blockade of the structural damage) in RA is still ongoing and will need treatment approaches, which are not exclusively confined to blocking a particular cytokine, receptor, or auto-reactive B or T cell involved in disease progression. To this end exciting treatment alternatives and drug targets are on the horizon that may become available to patients in the future.

Federalists and Anti-Federalists Essay -- History Historical Politics

The Constitution, when first introduced, set the stage for much controversy in the United States. The two major parties in this battle were the Federalists and the Anti-Federalists. The Federalists, such as James Madison, were in favor of ratifying the Constitution. On the other hand, the Anti-Federalists, such as Patrick Henry and Richard Henry Lee, were against ratification. Each party has their own beliefs on why or why not this document should or should not be passed. These beliefs are displayed in the following articles: Patrick Henry's "Virginia Should Reject the Constitution," Richard Henry Lee's "The Constitution Will Encourage Aristocracy," James Madison's "Federalist Paper No. 10," and "The Letters to Brutus." In these documents, many aspects of the Constitution, good and bad, are discussed. Although the Federalists and Anti-Federalists had very conflicting views, many common principals are discussed throughout their essays. The preservation of liberty and the effec ts of human nature are two aspects of these similarities. Although the similarities exist, they represent and support either the views of the Federalists or the Anti-Federalists. Patrick Henry makes his views very clear in his Letter. He is obviously against ratifying the Constitution. His main argument's consists of the sovereignty of the states, the system of checks and balances and the senate, the leaning towards a monarchy, and absolute power. Henry thinks that the uniting of all the states under one government would take away the sovereignty of the states. He states that, "Here is a resolution as radical as that which separated us from Great Britain. It is radical in this transition; our rights and privileges are endangered, and the sove... ...he other hand, Madison discusses the topic of liberty in that it is what fuels factions. He says that removing liberty is one of the only ways to destroy a faction. He proceeds to state that this is not probable, and that factions can not be destroyed, but we must control their consequences in order to have a stable government. Madison believes that the Constitution preserves man's liberty by fairly representing them in a central government. All of the topics discussed in these essays are very relevant to their respective causes. They are all backed up with valid information and examples. These essay's were written by very respectable men and show much insight on the subject of whether or not the Constitution should be ratified. The Federalists and Anti-Federalists had very opposing views, but used some of the same topics to support their point of views.

Inclusion of Children with Disabilities Essay -- Education School Spec

Inclusion of Children with Disabilities Along with many other topics of special education, the topic of inclusion has been surrounded by uncertainty and controversy for as long as the concept has been around. This controversy may stem from the fact that inclusion is expensive and experts disagree about how much time disabled students should spend in regular classrooms (Cambanis, 2001). Although this topic is controversial, it cannot be ignored. Inclusion will, at some point, affect 1% of all children born each year, who will have disabilities and the families and educators they will come in contact with (Stainback, 1985). There are two major federal laws that deal with the education of children with special needs. One of these laws is, The Individuals with Disabilities Education Act, also known as IDEA (W.E.A.C, 2001). This law passed in 1975, was the first act to guarantee all students with disabilities a public education (Kluth, Villa & Thousand, 2001). This law requires that the school district supply an IEP, individualized education program (Merritt, 2001), for every child with disabilities. This law also requires that the IEP team consider placing each child in the least restrictive environment possible (W.E.A.C, 2001). The least restrictive environment possible refers to the environment that would benefit the handicapped student the most, both academically and socially. The IEP team usually considers three possibilities for the student. One possibility is that of a self-contained classroom, where the student would be in a class with all disabled students and be taught by special education teachers. A second possibility is that the student be placed in a general education classroom for half of the... .... Learning Disability Quarterly, 24(4), pp.265-74. Retrieved March 11, 2002 from WilsonSelect Database. Palmer, David S., Fuller, Kathy., Arora, Tina. (2001). Taking Sides: Parent View on Inclusion for Their Children with Severe Disabilities. Exceptional Children, 67(4), pp.467-484. Retrieved March, 11, 2002 from WilsonSelect Database. Choate, Joyce S. (1997). Successful Inclusive Teaching- Proven Ways to Detect and Correct Special Needs. Massachusetts: Allyn& Bacon. Stainback, Susan & William. (1985). Integration of Students with Severe Handicaps into Regular Schools. Virginia: The Council for Exceptional Children. Special Education Inclusion. (2001). Retrieved February 25, 2002 from http://www.weac.org.htm Active Inclusion-Facilitating Active Inclusion in Secondary Education. (2000). Retrieved February 25, 2002 from http://www.faise.com

A Definition of Collaborative vs Cooperative Learning Essay

I have been searching for many years for the Holy Grail of interactive learning, a distinction between collaborative and cooperative learning definitions. I am getting closer to my elusive goal all the time but I am still not completely satisfied with my perception of the two concepts. I believe my confusion arises when I look at processes associated with each concept and see some overlap or inter-concept usage. I will make a humble attempt to clarify this question by presenting my definitions and reviewing those of other authors who have helped clarify my thinking. Collaboration is a philosophy of interaction and personal lifestyle whereas cooperation is a structure of interaction designed to facilitate the accomplishment of an end product or goal. Collaborative learning (CL) is a personal philosophy, not just a classroom technique. In all situations where people come together in groups, it suggests a way of dealing with people which respects and highlights individual group members’ abilities and contributions. There is a sharing of authority and acceptance of responsibility among group members for the groups actions. The underlying premise of collaborative learning is based upon consensus building through cooperation by group members, in contrast to competition in which individuals best other group members. CL practitioners apply this philosophy in the classroom, at committee meetings, with community groups, within their families and generally as a way of living with and dealing with other people. Cooperative learning is defined by a set of processes which help people interact together in order to accomplish a specific goal or develop an end product which is usually content specific. It is more directive than a collaboratve system of governance and closely controlled by the teacher. While there are many mechanisms for group analysis and introspection the fundamental approach is teacher centered whereas collaborative learning is more student centered. Spencer Kagan in an article in Educational Leadership (Dec/Jan 1989/1990) provides an excellent definition of cooperative learning by looking at general structures which can be applied to any situation. His definition provides an unbrella for the work cooperative learning specialists including he Johnsons, Slavin, Cooper, Graves and Graves, Millis, etc. It follows below: â€Å"The structural approach to cooperative learning is based on the creation, analysis and systematic application of structures, or content-free ways of organizing social interaction in the classroom. Structures usually involve a series of steps, with proscribed behavior at each step. An important cornerstone of the approach is the distinction bet ween â€Å"structures† and â€Å"activities†. â€Å"To illustrate, teachers can design many excellent cooperative activities, such as making a team mural or a quilt. Such activities almost always have a specific content-bound objective and thus cannot be used to deliver a range of academic content. Structures may be used repeatedly with almost any subject matter, at a wide range of grade levels and at various points in a lesson plan. † John Myers (Cooperative Learning vol 11 #4 July 1991) points out that the dictionary definitions of â€Å"collaboration†, derived from its Latin root, focus on the process of working together; the root word for â€Å"cooperation† stresses the product of such work. Co-operative learning has largely American roots from the philosophical writings of John Dewey stressing the social nature of learning and the work on group dynamics by Kurt Lewin. Collaborative learning has British roots, based on the work of English teachers exploring ways to help students respond to literature by taking a more active role in their own learning. The cooperative learning tradition tends to use quantitative methods which look at achievement: i. e. , the product of learning. The collaborative tradition takes a more qualitative approach, analyzing student talk in response to a piece of literature or a primary source in history. Myers points out some differences between the two concepts: â€Å"Supporters of co-operative learning tend to be more teacher-centered, for example when forming heterogeneous groups, structuring positive inter- dependence, and teaching co-operative skills. Collaborative learning advocates distrust structure and allow students more say if forming friendhip and interest groups. Student talk is stressed as a means for working things out. Discovery and contextural approaches are used to teach interpersonal skills. † â€Å"Such differences can lead to disagreements†¦. I contend the dispute is not about research, but more about the morality of what should happen in the schools. Beliefs as to whast should happen in the schools can be viewed as a continuum of orientations toward curriculum from â€Å"transmission† to â€Å"transaction† to â€Å"transmission†. At one end is the transmission position. As the name suggests, the aim of this orientation is to transmit knowledge to students in the form of facts, skills and values. The transformation position at the other end of the continuum stresses personal and social change in which the person is said to be interrelated with the environment rather than having control over it. The aim of this orientation is self-actualization, personal or organizational change. † Rocky Rockwood (National Teaching and Learning Forum vol 4 #6, 1995 part 1) describes the differences by acknowledging the parallels they both have in that they both use groups, both assign specific tasks, and both have the groups share and compare their procedures and conclusions in plenary class sessions. The major difference lies in the fact that cooperative deals exclusively with traditional (canonical) knowledge while collaborative ties into the social constructivist movement, asserting that both knowledge and authority of knowledge have changed dramatically in the last century. â€Å"The result has been a transition from â€Å"foundational (cognitive) understanding of knowledge†, to a nonfoundational ground where â€Å"we understand knowledge to be a social construct and learning a social process† (Brufee, Collaborative learning: Higher Education, Interdependence, and the Authority of Knowledge, 1993). Rockwood states: â€Å"In the ideal collaborative environment, the authority for testing and determining the appropriateness of the group product rests with, first, the small group, second, the plenary group (the whole class) and finally (but always understood to be subject to challenge and revision) the requisite knowledge community (i. e. the discipline: geography, history, biology etc. ) The concept of non- foundational knowledge challenges not only the product acquired, but also the process employed in the acquisition of foundational knowledge. â€Å"Most importantly, in cooperative, the authority remains with the instructor, who retains ownership of the task, which involves either a closed or a closable (that is to say foundational) problem ( the instructor knows or can predict the answer). In collaborative, the instructor–once the task is set– transfers all authority to the group. In the ideal, the group’s task is always open ended. † â€Å"Seen fr om this perspective, cooperative does not empower students. It employs them to serve the instructor’s ends and produces a â€Å"right† or acceptable answer. Collaborative does truly empower and braves all the risks of empowerment (for example, having the group or class agree to an embarrassingly simplistic or unconvincing position or produce a solution in conflict with the instructor’s). † â€Å"Every person, Brufee holds, belongs to several â€Å"interpretative or knowledge communities† that share vocabularies, points of view, histories, values, conventions and interests. The job of the instructor id to help students learn to negotiate the boundaries between the communities they already belong to and the community represented by the teacher’s academic discipline, which the students want to join. Every knowledge community has a core of foundational knowledge that its members consider as given (but not necessarily absolute). To function independently within a knowledge community, the fledgling scholar must master enough material to become conversant with the community. † Rockwood concludes: In my teaching experience, cooperative represents the best means to approach mastery of foundational knowledge. Once students become reasonably conversant, they are ready for collaborative, ready to discuss and assess,†¦. † Myers suggests use of the â€Å"transaction† orientation as a compromise between taking hard positions advocating either methodology. â€Å"This orientation views education as a dialogue between the student and the curriculum. Students are viewed as problem solvers. Problem solving and inquiry approaches stressing cognitive skills and the ideas of Vygotsky, Piaget, Kohlberg and Bruner are linked to transaction. This perspective views teaching as a â€Å"conversation† in which teachers and students learn together through a process of negotiation with the curriculum to develop a shared view of the world. † It is clear to me that in undertaking the exercize of defining differences between the two ideas we run the risk of polarizing the educational community into a we versus them mentality. There are so many benefits which acrue from both ideas that it would be a shame to lose any advantage gained from the student-student-teacher interactions created by both methods. We must be careful to avoid a one-size-fits-all mentality when it comes to education paradigms. As a final thought, I think it behooves teachers to educate themselves about the myriad of techniques and philosophies which create interactive environments where students take more responsibility for their own learning and that of their peers. Then it will become possible to pick and chose those methods which best fit a particular educational goal or community of learners.