Treatment of Down Syndrome using Haloperidol

Treatment of Down Syndrome using Haloperidol CLINICAL RESEARCH FACILITY APPLICATION Q1 Details of Main Contact: Title Name: Haloperidol in Down Syndrome and Sivaram Kumar Sivalingam Pandiyarajan Q2 Study title Treatment of Down Syndrome using Haloperidol Q3 Please provide an abstract or brief synopsis of the proposed study (Max 250 words). Haloperidol is an antipsychotic drug which exhibits high affinity towards dopamine D2 receptor antagonism. It also shows a slow receptor dissociation kinetics which is similar to phenothiazines. The drug is used in the treatment of schizophrenia were polymorphisms in the dopamine receptor genes showed the presence of psychotic phenomena or aggressive behavior. Down syndrome (DS) increases the risk of Alzheimers disease (AD) by 15% for the people who live 40 years are long. Problems related to behavior are not a general issue as in other syndromes associated with intellectual disability. 30% of children with DS have a mental illness. Anxiety and depression in early adulthood may develop for the people with DS. Studies indicate that polymorphisms in dopamine receptor D1 (DRD1) and dopamine receptor D3 (DRD3) genes in late-onset AD exhibit symptoms of psychotic phenomena or aggressive behavior in people. Haloperidol suppresses the ionic imbalance by blocking the beta-amyloid-induced ele vation of calcium in Alzheimer cells which showed a significant decrease in calcium cells. Studies also indicate that the symptoms of attention-deficit hyperactivity disorder (ADHD) in DS also showed the effects of executive function in children with DS about the dopamine receptor DRD4 gene linked to ADHD in people with DS. Hence, it is hypothesized that haloperidol can be used in the treatment of Down syndrome. Indicate your Word Count (Max 250 words). 215 Q4 Please outline what question(s) the study is designed to answer/primary measure of outcome (Max 150 words). The primary outcome of the study is to reduce the relapse of patients into psychosis due to down syndrome (DS). Reduction of relapse in DS due to psychotic breakdown which occurs similarly as in schizophrenia which indicates the activity of haloperidol in the prevention of diseases prognosis. During the study, details for questions such as the how the effect of haloperidol action on dopamine receptors reduce disease prognosis of DS, What is the mechanism of action of haloperidol in the treatment of DS?, Does haloperidol prevents the prognosis of DS by intervening the mechanism involved in Alzheimers disease (AD) or Attention-deficit hyperactivity disorder (ADHD)?, Etc. Indicate your Word Count (Max 150 words). 105 Q5 Indicate clearly how you will perform the study (include methods, materials, number of patients, demographics, statistics and all other matter that you consider important) (Max 1500 words). Haloperidol is an ethically approved drug which is already on the market and used for the treatment of schizophrenia, acute psychosis, Tourette syndrome, bipolar disorder, etc. Since haloperidol is ethically approved direct administration of the drug to the patients who have down syndrome (DS) can be performed, and observation study can be conducted. Human materials such as primary cell culture and organotrophic culture from a patient are required for the detailed understanding of the mechanism of action involved in the treatment of DS using Haloperidol. The mechanism of action should be compared with the Alzheimers disease (AD) and Attention-deficit hyperactivity disorder (ADHD) to analyze the effect on DS. Researchers have estimated that out of 1200 people one will suffer from DS in the United States this includes children, teens, and adults. Children with DS usually do not have mental retardation and a psychiatric disorder. 18% to 38% of children with DS currently have a possibili ty for the prevalence of the neurobehavioral and psychiatric disorder. During one of the research studies conducted regarding DS, determined that a pre-pubertal onset be found for children with DS presenting in the post-pubertal period which is the unique vulnerability period for specific psychiatric disorders. The Study Design is performed by randomized allocation where a parallel interventional model of drug assignment is proposed. The subject, investigator and outcome assessor are masked from the drug and placebo treatment using a double-blind method to achieve high efficiency and less interference. The primary purpose remained to be the treatment of the disease. The inclusion and exclusion criteria for the participants for involving the study was neglected of age (18 to 64 years) and sex (Male, Female, and others) as a criterion. In the inclusion criteria, the patient should be primarily diagnosed with DS and should be hospitalized with Standard Trisomy 21, Translocation, and Mosaicism DS. The patient should have been diagnosed with the illness for at least one year and should have gone psychological evaluations. At the most, the patient should be able to drop off of any antipsychotic medication for a period. There are two phases in the study of Haloperidol on DS. The DS outpatients who meet criteria for inclusion and exclusion is allowed to enter the Phase 1. A flexible dose of Haloperidol 1-5mg is given to the patients for 20 weeks of open acute treatment phase 1. An oral dose of 1 mg of Haloperidol is given daily, where the dose is titrated until the optimal dose is reached with an increase of 1 mg per titration. The optimal dose is fixed based on the optimal trade-off between side effects and efficacy. Phase 1 looks for patients who meet the criteria for clinical response and another exit the protocol and are treated with alternative medications openly. The patients who responded well in phase 1 are taken into Phase 2, where the random assignment of placebo-controlled continuation trial takes place for 24 weeks. Based on the severity and presence of psychosis the randomization is stratified where half of the patients takes haloperidol, and other patients receive a placebo. The Patient s who relapse with psychosis during Phase B will exit the protocol and receive extensive treatment. To attain the statistical significance and to achieve a normal distribution the alpha value is set as 0.1 and small minimum sample size of 99 participants is required to pilot this study. Repeated measures ANOVA is to be conducted at three major time-points in the week 10, week 20 and baseline. This analytic strategy is to be used to measures the efficacy as well as side effects, global cognition, and activities of daily living. Indicate your Word Count (Max 1500 words). 603 Q6 Indicate clearly the need to work with human materials for this research in terms of ethical approvals (Max 200 words). Haloperidol is an ethically approved drug which is already on the market and used for the treatment of schizophrenia, acute psychosis, Tourette syndrome, bipolar disorder, etc. Researchers have estimated that out of 1200 people one will suffer from Down syndrome in the United States this includes children, teens, and adults. Hence, the need of drug for the treatment of down syndrome (DS) is raising. Since haloperidol is ethically approved direct administration of the drug to the patients who have DS can be performed, and observation study can be conducted. The study requires less attention of rules and guidelines for ethical issues. Since there is no proper animal model for DS and obtaining, culturing, and preservation of primary cell culture and organotrophic culture from patients with DS is tough. Hence the need for human clinical trials is necessary for testing the drug haloperidol for the treatment of DS. Indicate your Word Count (Max 200 words). 147

An Occurrence at Owl Creek Bridge by Ambrose Bierce Essay -- English L

An Occurrence at Owl Creek Bridge by Ambrose Bierce 'An Occurrence at Owl Creek Bridge' by Ambrose Bierce is a 19th Century mystery story that is set at the time of the American Civil War (1861-1865) when the Slave owning Confederate States in the South engaged in conflict with the Federal Government of the USA. The story focuses on a character called Peyton Farquhar, whom is about to be summarily hung for trespassing on the Owl Creek Bridge; his fate is to be hung from that same bridge. The story ends with a curious twist in the plot. The main part of the story is set in Farquhar's mind, though whilst reading the reader is unsure (despite careful, hidden hints placed by Bierce) of this fact. Only at the end when it is clearly stated that Farquhar is hanging lifelessly with a broken neck from the bridge that the reader will become conclusively aware of this. It is divided into three parts, which I will analyse, in detail, separately. Part I ====== 'An Occurrence at Owl Creek Bridge' 'begins powerfully by introducing a man, whom is not named until later on in the tale. This obviously adds to the mystery. It describes with detail of him in somewhat a predicament ~ " hands behind his back", " wrists bounds with a cord", "rope closely encircled his neck". Words of such like are of a lexical set of entrapment and give the impression that the man in question is in danger and is unable to break free. Next, the reader learns that "executioners" (also are soldiers from federal army) are present that show the man has committed a crime, so is a condemned man. It raises questions as to why he is there, and forces the reader to continue reading. Bierce sustains more mystery by not revealing his crime until furt... ...y~ " Ah, how beautiful she is! He springs forward with extended arms". Bierce lures the reader into thoughts of joy by remarking how beautiful the wife is. Suddenly, Bierce stops his complex illusions and proves that proves the prior Part III was not reality, set in the min of Farquhar~ "his body swung gently from side to side beneath the timbers of the Owl Creek Bridge. Conclusion ========== Bierce has a unique style to pull the reader into the story. To name a few techniques, his complex illusions keep the audience in suspense, his detailed descriptions allow the reader to picture all aspects of the story and the dividing of the story into three separate parts help them to stay focused. These all work together to provide a compelling, inspiring and powerful story. 'An Occurrence at Owl Creek Bridge' is a great example how the mind can be deceptive.

An Essay on the Characteristics and Development of Ancient City-States Essay

A city-state is defined as an independent or autonomous entity whose territory consists of a city which is not administered as part of a local government. Through reading the articles of Larson, Westenholz, and Neihmer it becomes apparent that city-states differ depending on the region and time they are in, and the purpose they serve. The three specific examples that come to mind are the Phoenicians, Assyrians, and the Sumerians. All three of these had unique characteristics that define each society; however, all three societies displayed enough similarities to make them definable as ancient city-states. One of the defining characteristics of a city-state is the fact that it is a self-governing and self-sufficient entity. Ancient city-states provided the first clear evidence for social stratification and most city-states contained a ruling family or dynasty, which controlled the city-state and it’s surrounding hinterlands by managing the land, water, and other natural resources. Each city state also contained a council of elders which helped the ruling family serve as a controlling body of local policy. However in Assyrian city-states there also existed a year-eponymy, which was a person who was elected for a single year to serve as the head of the city hall. He acted as the head of the city and carried out the executive orders form the higher officials suchas the king and the elders. In Sumerian city states, kings were referred to as â€Å"ensi† or â€Å"lugal† which were names that were meant to display to citizens his power and importance, and made his rule indisputable within society. Kings were relied upon to build not only monumental structures and temples for their respective deities, but also to maintain a functional infrastructure. In Phoenician city states, The king was landlord of pretentious places and sacrificial buildings. This display exists in many city- states and not only in Phoenician culture. The king demonstrated his power through buildings such as tombs and temples, but however, he was also the leading figure in charge of maintenance of public places, and in most cities, the defensive wall. There is sufficient evidence of city-walls consistently across all ancient city-states, but the reason these walls existed remains unclear. There is no archaeological evidence of warfare, or conflict between city- states. One of the most logical reasons for these walls to exist was to serve a symbolic purpose because the interior area would be posses a more clear political identity. The Assyrians, in dealing with enemies, took a unique and strict political regime that limited trade and dealings with other city-states, and as evidenced by the archaeological record, in a letter. Their particular rule stated that if any merchant traded with a Akkadian Amorite or a Subariean, then the merchant would be put to death. Laws such as this one established a clear political stance that many cities held on many issues concerning interactions with outsiders. Though The city ruler acted as the city god’s human deputy and managed the assets of the city as a whole. there is also sufficient evidence for long- distance trade. City- states developed in Phoenician, Assyrian, and Sumerian society as important trade resources and had a significant impact on culture. Prominent city-states were key to cultural development because they were able to support local artisans and were key centers of trade, which enabled different cultures to influence one another. Sumerian city-states were located in key trade locations because their own agricultural opportunities were scarce, and they heavily relied on the trade of barley, beer and textiles to other places in order to obtain food resources form elsewhere in order to support their population. In Assyrian society, the economy was controlled by ruling families and therefore, trade was regulated depending on the ruling class. These city-states productivity was dependent upon the weather for that year, so trade would fluctuate depending on the success of the season. For Phoenician city- states, there is sufficient archaeological evidence for long- distance trade, shown in the influence and presence of foreign art and style. Furthermore, archeological evidence is supplied in the discovery of cylinder seals, which were used to ensure the authenticity of the item being traded or shipped, and ensure its condition, if the seal remained unbroken. Key developments in ancient city- states are displayed in the changes of city plan’s and architecture, as well as further developments in trade. In some cases, cities were set up in tribute to a specific deity. These cities were mainly located on a hill, with a temple on the highest point, with the rest of the city built around the center temple. These temples not only served as places of religious worship and practice, but also served as cultural and economic centers. A distinguishing characteristic of many ancient city- states is, dominant palaces, temples†¦of sometimes monumental size and form†¦lie next to tightly knit living quarters traversed by an irregular network of streets, and in most cases these cities had irregular and unique city plans from one another. The proximity of the households to the temple showed the importance and the involvement of the temple in the daily life of the citizens. Furthermore, the layout of the city also demonstrates social stratification.

Definition and Examples of Marginal Modals in English

In English grammar, a marginal modal is a verb (such as dare, need, used to, ought to) that displays some but not all of the properties of an auxiliary. The marginal modals all have meanings that are related to necessity and advice.  A marginal modal can be used as either an auxiliary or a main verb. Examples I think we ought to read only the kind of books that wound and stab us.(Franz Kafka, letter to Oscar Pollack, January 27, 1904)I used to live in a room full of mirrors.All I could see was me.(Jimi Hendrix, Room Full Of Mirrors)For Children: You will need to know the difference between Friday and a fried egg. Its quite a simple difference, but an important one. Friday comes at the end of the week, whereas a fried egg comes out of a chicken.(Douglas Adams, The Salmon of Doubt: Hitchhiking the Galaxy One Last Time. Crown, 2002) Characteristics of Marginal Modals Neither the marginal modal nor any of the modal idioms form past or present participles (thus *I have oughted to work hard, *I am oughting to work hard). And although very few semi-auxiliaries participate in compound tenses, a few function adequately as perfects (I have been able/going to/obliged/willing to work hard, I have been about to work hard on several occasions, I have had to work hard) and only two are unquestionably acceptable as progressives (I am being obliged to work hard, I am having to work hard). As a general rule, semi-auxiliaries are reluctant to enter compound tenses.(Richard V. Teschner and Eston E. Evans, Analyzing the Grammar of English, 3rd ed. Georgetown University  Press, 2007) Dare and Need As Marginal Modals ​​As modal verbs, dare and need take a bare infinitive complement in negated and/or inverted structures. They do not have third person singular forms.(128) Or darent you ask?(129) You neednt read every chapter.(130) And dare I suggest that that is the match-winner?(131) Nor need I look further than my own city of Sheffield.As a marginal modal verb need has no past tense: we cannot say, for example *He needed read every chapter. It expresses necessity which is clearly a central modal meaning. Dare is not obviously modal from the point of view of meaning, though it is forward-looking, and is sometimes regarded as instantiating dynamic modality, due to the fact that the act of daring relates to the subject of the clause.(Bas Aarts, Oxford Modern English Grammar. Oxford University Press, 2011)The verb dare . . . is an odd little word. . . . Sometimes its called a marginal modal, but I prefer the description quasi modal. Either label, dare hovers between being an ordinary ga rden-variety verb meaning to challenge and one of these more abstract and grammatically complex verbs conveying a judgment about likelihood--and its this double life that gives rise to some fairly eccentric behaviour. Consider how it forms a negative. Do you say I darent (pronounced darent or dairnt), I dare not, or I dont care? T.S. Eliot might have chosen to phrase the question in The Love Song of J. Alfred Prufrock as Do I dare to eat a peach? but some of you might prefer Dare I eat a peach? The word order is different, and its also variable whether or not you follow dare with to.Colloquial English is full of these quasi modals. The verb need is one, and so are contracted expressions such as gonna, wanna and halfta. But one of my current favourites is better as in I better do it.(Kate Burridge, Weeds in the Garden of Words: Further Observations on the Tangled History of the English Language. Cambridge University  Press, 2005) Used to As a Marginal Modal Used to occurs only in the past tense form, and always includes to. We do not say * I use to go or * I used go. In the negative form, some people prefer it as a main verb (but are often uncertain about the spelling): I didnt (use(d) to go. Others prefer it as an auxiliary verb: I usent/used not to go (especially in Britain).(David Crystal, Rediscover Grammar, 3rd ed. Longman, 2004)[T]here are a number of marginal auxiliaries (dare, need, ought to, used to) that share some of the characteristics of the auxiliaries and a larger group of semi-auxiliaries (auxiliary-like verbs) that convey similar notions of time, aspect, and modality (e.g.: be going to, have to, had better).(Sidney Greenbaum, Oxford English Grammar. Oxford University  Press, 1996) Also Known As: marginal auxiliary, marginal modal auxiliary, semi-modal, quasi-modal, semi-auxiliary