Anti-Inflammatory Drug Tests

Anti-Inflammatory Drug Tests The method described by Lorke with slight modification was used to determine the safety of the MEA. Briefly, normal healthy male mice were divided into groups of five mice in each cage. MEA (100 and 1000 mg/kg) or vehicle were intraperitoneally administered. Access to food and water, toxic symptoms and the general behavior of mice were observed continuously for 1 h after the treatment, intermittently for 4 h, and thereafter over a period of 24 h. The mice were further observed for up to 14 days following treatment for any signs of toxicity and mortality. Result Over the study duration of 14 days, there were no deaths recorded in the groups of mice given 100 or 1000 mg/kg IP of MEA. During the observation period, MEA administration did not induce any variations in the general appearance or toxic signs in the animals. The writhing test has long been used as a screening tool for the assessment of analgesic or anti-inflammatory properties of new substances (Collier et al., 1968). This method presents a good sensitivity, although it has poor specificity. To avoid misinterpretation of the results, in the present study the antinociceptive effects of MEA were confirmed in the formalin test, a model of inflammatory pain which has two distinctive phases which may indicate different types of pain (Hunskaar and Hole, 1987). The early and late phases of formalin test have obvious differential properties, and therefore this test is useful not only for assessing the analgesic substances, but also for elucidating the mechanism of analgesia (Shibata et al., 1989). The early phase,  named non-inflammatory pain, is a result of direct stimulation of nociceptors and reflects centrally-mediated pain; the late phase,  named inflammatory pain, is caused by local inflammation with a release of inflammatory and hyper algesic mediators (Hunskaar  and Hole, 1987). The thermal model of the tail-flick test is considered to be a spinal reflex, but could also involve higher neural structures, and therefore this method identifies mainly central analgesics (Jensen and Yaksh, 1986; Le Bars et al., 2001). Due to their implication in virtually all human and animal diseases, inflammation and pain have become the focus of global scientific research. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids have necessitated the search for new drugs with minimal side effects (Dharmasiri et al.,2003; Vittalrao et al., 2011). The current trend of research is the investigation of medicines of plant origin because of their affordability and accessibility with minimal side effects. The thermal model of the tail-flick test is considered to be a spinal reflex, but could also involve higher neural structures, and therefore this method identifies mainly central analgesics (Jensen and Yaksh, 1986; Le Bars et al., 2001). The analgesic activity of Cyathula prostrata in this study was investigated using the hot plate and mouse writhing tests. The hot plate test is useful for the evaluation of centrally acting analgesics which are known to elevate the pain threshold of mice towards  heat (Hiruma-Lima et al., 2000). It also indicates narcotic involvement with opioid receptor (Turner, 1965). The writhing model is a sensitive method for screening peripheral analgesic efficacy agents and it is more sensitive to non-steroidal analgesics (Collier et al., 1963). The analgesic effect of acetic acid is due to the liberation and increased level of several mediators such as histamine and serotonin which act by stimulation of peripheral nociceptive neurons (Cui et al., 2010). Over the centuries, phytopharmaceuticals have been utilized by different communities of the world [1]. Acetic acid-induced writhing is a well recommended protocol in evaluating medicinal agents for their analgesic property. The pain induction caused by liberating endogenous substances as well as some other pain mediators such as arachidonic acid via cyclooxygenase, and prostaglandin biosynthesis [10,23]. This pain paradigm is widely used for the assessment of peripheral analgesic activity due to its sensitivity and response to the compounds at a dose which is not effective in other methods. The local peritoneal receptor could be the cause of abdominal writhings [24]. Pain sensation in acetic acid induced writhing paradigm is elicited by producing localized inflammatory response due to release of free arachidonic acid from tissue phospholipids via cyclo-oxygenase (COX), and producing prostaglandin specifically PGE2 and PGF2ÃŽ ±, the level of lipoxygenase products may also increases in peritoneal fluids [10,23]. These prostaglandin and lipoxygenase products cause inflammation and pain b y increasing capillary permeability. The substance inhibiting the writhings will have analgesic effect preferably by inhibition of prostaglandin synthesis, a peripheral mechanism of pain inhibition [23]. Thermal nociception models such as hot plat and the tail immersion tests were used to evaluate central analgesic activity. The management of pain and inflammation related problems is a real challenge that people face daily. Although several drugs are available for these conditions, medicinal plants are believed to be an important source of new chemical substances with potential therapeutic effects (Gupta et al., 2006). Formalin test The formalin test was carried out as described by Santos and Calixto, (1997). Groups of mice (n=5) were treated with HAAE (150 and 200 mg/kg), HAME (150 and 200 mg/kg), Aspirin (100 mg/kg), Morphine (10 mg/kg) and distilled water. Formalin (1% v/v) was injected into the sub-plantar region of the right hind paw of the animals, one hour post treatment. The duration of paw licking was measured for 0-5 minutes (neurogenic phase) and 15-30 minutes (inflammatory phase) after formalin administration. Result The formalin test exhibited the characteristic biphasic response. Phase 1 response which was recorded from the time of formalin injection and 5 minutes post-injection was not affected by either extract at either dose level. Morphine however, showed significant (p minutes post formalin injection. The extracts of HAAE (150 mg/kg and 200 mg/kg) and HAME (150 mg/kg and 200 mg/kg) as well as aspirin and morphine showed significant (p Acetic acid induces pain by the release of endogenous mediators of pain such as prostaglandin through the activity of cyclooxygenase (COX) (Satyanarayana et al., 2004; Ballou et al., 2000). Therefore this model of pain should be inhibited by peripheral analgesics through the inhibition of COX activity. Our results therefore show that the higher doses of HAAE and HAME have peripheral analgesic properties similar to aspirin by inhibition of the release of endogenous pain mediators The formalin test is said to be a model of pain which closely resembles clinical pain compared to the other nociceptive models (Tjolsen and Hole, 1997). This test has two distinct phases: the first phase (neurogenic pain) due to direct chemical stimulation of nociceptors, results from the stimulation of myelinated and unmyelinated nociceptive afferent fibers, mainly C fibers, which can be suppressed by opioid analgesic drugs like morphine (Sayyah et al., 2004). The second or late phase seems to be an inflammatory response which elicits inflammatory pain and can be inhibited by anti-inflammatory drugs (Young at al., 2005). The second phase is caused by the release of inflammatory mediators such as prostaglandins and histamine in the peripheral tissues, as well as functional changes in the neurons, of the spinal cord which may facilitate transmission in the spinal cord (Franca et al., 2001; Garcia et al., 2004) Cotton pellet induced granuloma tissue formation FPEO, BPEO and diclofenac sodium were orally administered for 16 consecutive days in Groups III-VII. On eighth day, the animals (Groups II-VII) were mildly anaesthetised with ether, four sterile cotton pellets (50 mg) were subcutaneously implanted in the dorsal region of the rats and two at the axilla and two at the groin regions. On 16th day, all the rats were killed using anaesthetic ether and the cotton pellets were dissected out without affecting the surrounding granuloma tissues (Winter and Porter 1957). Chronic inflamed tissues (from axilla and groin regions) were excised and stored in 0.9% saline at -20_C for biochemical analysis. The moist pellets were weighed and then dried at 60_C for 48 h and then again reweighed. The percentage reduction in cotton pellets weight of the test samples was observed and compared with that of respective cotton pellet and diclofenac sodium treated groups. This provides a measure to assess the anti -inflammatory effect of the test samples. Experimental design Seven groups were employed in the present anti-inflammatory study. Each group consists of six rats and experimental protocol included 16 days study. Each group of animals was employed with sterile cotton pellets (50 mg each) implantation in the dorsal region of rats at eighth day. Group I (vehicle control group): 1% of carboxy methyl cellulose (1 mL, p.o.) was administered to the rats for 16 consecutive days. Group II (negative control group): four sterile cotton pellets, 50 mg each were implanted in the dorsal region of rats at eighth day. Group III (positive control group): reference standard drug and diclofenac sodium (12.5 mg/kg, p.o.) were administered to the rats for 16 consecutive days. Groups IV-VII (test groups): rats were pretreated with free and bound phenolic compounds of E. officinalis (20 and 40 mg/kg, p.o.) for 16 consecutive days. Result Effect of E. officinalis on granulomatous tissue formation Table 1 shows the effect of FPEO and BPEO on granulomatous tissue changes due to cotton pellet induced chronic inflammation. Changes in the cotton pellets weight (wet weight-dry weight) of the test samples were compared with the cotton pellet and diclofenac sodium (12.5 mg/kg) treated groups. Pretreatment (i.e. on days 1-8) of diclofenac and the phenolic fractions of E. officinalis did not show any behavioral changes. Both the fractions have shown reduction in granulomatous tissue mass as compared to cotton pellet treated group. However, only high doses (40 mg/kg) of each fraction have shown  significant (p.05) reduction which was comparable to that of diclofenac sodium pretreated group. The hot plate method is very effective for evaluating drugs possessing analgesic property, which act centrally (Vale et al., 1999; Haque et al., 2001; Silva et al., 2003; Al-Naggar et al., 2003). Prolongation of reaction time in hot plate test inferred possible central analgesic effects of the oil. The oil increased the reaction time significantly at the dose levels used compared to control group. Acetic Acid-induced writhing has been used to evaluate drugs possessing peripheral analgesic effects (Koster et al., 1959; Viana et al., 2000). Acetic acid has been reported to cause hyperalgesia by liberating endogenous substances such as prostaglandins, leukotrieines, 5-HT, histamine, kinins, H+ and K+, etc. which have been implicated in the mediation of pain perception (Forth et al., 1986; Rang et al., 1999). Yin et al (2003) reported that many studies have shown that the earlier phase (1st phase) of formalininduced pain reflects the direct effect of formalin on nociceptors whereas the late phase (2nd phase) reflects inflammatory pain, which has been linked to prostaglandin synthesis (Hong and Abbot, 1995; Yin, et al., 2003). Opioid analgesics have been reported to possess antinociceptive effects in both phases having more effect at the 2nd phase (Le Bars et al., 2001). Non-steroidal anti-inflammatory drugs (NSAIDS) such as indomethacin is said to be effective only in the 1st phase especially if the formalin is injected at high concentration (Yashpal and Coderre, 1998). In this study, the oil dose-dependently inhibited nociception induced in the Formalin Test significantly compared to control group in the 1st phase (neurogenic) and 2nd phase (inflammatory). These results therefore further suggest that the oil contain constituents that exhibit anti-inflammatory properties Commonly used Non-Steroidal anti-inflammatory Drugs (NSAID) such as aspirin and indomethacin are widely used to reduce swelling associated with pain and inflammation through inhibition of prostaglandin synthesis by direct effect on cyclo-oxygenase (COX) in the arachidonic acid (AA) metabolism (Amos et al., 2001; Nwafor and Okwuasaba, 2003) Inflammation is a disorder involving localized increases in the number of leukocytes and a variety of complex mediator molecules [4]. Prostaglandins are ubiquitous substances that indicate and modulate cell and tissue responses involved in inflammation. Their biosynthesis has also been implicated in the pathophysiology of cardiovascular diseases, cancer, colonic adenomas and Alzheimers disease [5,6]. Medicinal plants are believed to be an important source of new chemical substances with potential therapeutic effects [7,8]. The research into plants with alleged folkloric use as pain relievers, antiinflammatory agents, should therefore be viewed as a fruitful and logical research strategy in the search for new analgesic and anti-inflammatory drugs [9]. Acute toxicity test The animals were divided into six groups containing eight animals in each group. MEPA was suspended in normal saline and administered orally as a single dose to groups of mice at different concentrations (500, 750, 1000, 1250, 1500 and 2000 mgkg-1 b.w). These animals were observed for a 72 h period. The number of deaths was expressed as a percentile and the LD50 was determined by probit a test using the death percentage versus the log dose [12]. Result Acute toxicity test In the acute toxicity assay no deaths were observed during the 72 h period at the doses tested. At these doses, the animals showed no stereotypical symptoms associated with toxicity, such as convulsion, ataxy, diarrhoea or increased diuresis. The median lethal dose (LD50) was determined to be higher than highest dose tested i.e., 2.0 gkg-1 b.w. Cotton pellet-induced granuloma The cotton pellets-induced granuloma in rats was studied according to the method DArcy et al., 1960 [16]. The animals were divided into four groups of six animals in each group. The rats were anaesthetized and sterile cotton pellets weighing 10  ± 1 mg were implanted subcutaneously into both sides of the groin region of each rat. Group I served as control and received the vehicle (0.9% NaCl, 5 mlkg-1 b.w. The extract MEPA at the concentration of 250 and 500 mgkg-1 b.w was administered orally to groups II and III animals for seven consecutive days from the day of cotton pellet implantation. Group IV animals received indomethacin at a dose of 10 mgkg-1 b.w for the same period. On 8th day the animals were anaesthetized and the pellets together with the granuloma tissues were carefully removed and made free from extraneous tissues. The wet pellets were weighed and then dried in an oven at 60 °C for 24 h to constant weight, after that the dried pellets were weighed again. Increment in the dry weight of the pellets was taken as a measure of granuloma formation The antiproliferative effect of MEPA was compared with  control. Statistical analysis The values were expressed as mean  ± S.E.M. The statistical significance was determined by using the student t-test [17]. Values of P Result Cotton pellets-induced granuloma The effects of MEPA and indomethacin on the proliferative phase of inflammation are shown in table 1. A significant reduction in the weight of cotton pellets was observed with MEPA (250 and 500 mgkg-1 b.w) compared to the vehicle treated rats. However the degree of reduction was less than the effect caused by indomethacin. The cotton pellet method is widely used to evaluate the transudative and proliferative components of the chronic inflammation. The wet weight of the cotton pellets correlates with the transuda; the dry weight of the pellets correlates with the amount of the granulomatous tissue [20,21]. Administration of MEPA (250 and 500 mgkg-1 b.w) and indomethacin (10 mgkg-1 b.w) appear to be effective in inhibiting the wet weight of cotton pellet. On the other hand, the MEPA effect on dry weight of the cotton pellet was almost near to that of indomethacin. These data support the hypothesis of the greater effect of the MEPA on the inflammation in rats. This effect may be due to the cellular migration to injured sites and accumulation of collagen an mucopolysaccharides.

Coach of the Army Crew

Army Crew Case Analysis Coach of the Army Crew; Coach P. selected the top eight rowers for the Varsity boat after a long series of objective tests measuring each member’s speed, strength and coordination. The Varsity team had a clear advantage over the Junior Varsity team. So, how could Junior Varsity team beat the Varsity team in two-thirds of the time in practice races? There are obvious reasons behind the bad performance of the Varsity team. Coach P. lacking a leadership couldn’t see the signs of Varsity team having serious problems as a team.The problem with Coach P. ’s coaching mistake started with the team selection process of Varsity team members. He managed to measure individual performances successfully by using ergometer and weight records. However, as important as individual skills were, it was crucial for the eight individual members to be a team and synchronize their rowing. His performance and team building criteria lacked personality factors. Howev er, rowing needs a perfect teamwork and mental strength of the crew members. U. S.Olympic Committee’s research project showed that the master coaches those who were most experienced and successful tended to focus on psychological variables as the most important criteria for a successful crew team whereas novice coaches tended to focus on technique just like Coach P. did. Selecting a team solely dependent on individual technical performance resulted in very serious problems among team members. Coach P. lacking leadership skills had no vision about the team having serious trust and coordination problems.Just before National championships races, he –for the first time- included personality dimensions to analyze the team. It revealed that the Varsity team had no team leaders and had team disrupters instead. He brought in an external party to improve their confidence, concentration and motivation of the Varsity team which the Varsity team labeled it as â€Å"touch-feelyâ⠂¬ . Other than bringing in an external party, he should have acted as a leader and make the best decision for the group by using Rational Decision Making Model steps: first by identifying the problem, generating solutions, selecting the best solution and implementing it.He should have showed a transformation leadership which would increase acceptance and support from the Varsity Team. Each set of the transformational leadership behavior was very crucial for the disrupted team: * Inspirational motivation (establishing a vision using emotion): It is very obvious that the Varsity team had superior performance individually and they can perform much better if they believe in their team. However, they are demotivated and lost their beliefs in the team. Coach P. encouraged competition between JV and V groups which affected Varsity team negatively.Other than creating a tension between teams, he should have motivated each team separately and should have built close relationships with membe rs and provided an open and direct communication with them. * Idealized influence (sacrificing for the greater good): Team disrupters decreased the motivation of the team and the team had no leaders. Coach P. relied on third parties such as Center of Enhanced Performance (CEP) and asked the group â€Å"What is your solution? † other than trying to make the best decision himself and then take the right step.For the greater good of the team, he should have demoted the team disrupters. For the rest of the team she should have worked with each member individually to set their goals and increase their motivation. * Individualized consideration (providing support): The Varsity team’s most important problem is motivation and lacking a team spirit. To overcome this problem, Coach P. should have showed his support and provide open communication with the team. Instead, he tried to find the â€Å"right combination† by switching members of the teams and causing a tension am ong Varsity and JV boats.He should have realized from the very beginning that the problem is not about physical but it was psychological. By trying different combinations, he made the team’s psychology even worse. * Intellectual stimulation (encouraging employees to question the status quo): Coach P. should have let them negotiate and come to an agreement about the situation but it was very late for him to hold a group meeting just before National championships. Coach P. should have realized the trust and coordination problems of the team and should resolve the problems much earlier.As a good leader, he should have built the team depending on both physical and personality factors in the first place. He should have demoted team disrupters for better teamwork and motivation among the rest of the team members. To resolve the conflict between Varsity team, he should have provided a better communication among them. That way, they would have come to an agreement without any support from an external party like CEP. To create a team spirit, he should have done team building games and activities and make them socialize with each other. Both the team members and the coach don’t know and trust each other.Just like basketball coach, Coach K. ’s leadership style he should have been a loved leader who creates personal interaction and drives performance through respect. He should have built trust and respect among teammates and himself. After achieving these goals, it is very important to motivate the team to achieve a better performance. For Varsity team, following Locke’s Goal Setting Theory, creating SMART (goals that are specific in their orientation, measurable, achievable, relevant and time-based) and right level of goals would increase the motivation and effort.Returning to case, Coach P. should not switch Varsity and Junior Varsity boats even though Varsity will perform badly in the Championships. That way, he will show his support and tru st to Varsity team. If he chooses JV team to compete, he might lose the Varsity team forever. He shouldn’t switch team members other than the team disrupters. Varsity boat has a clear advantage over Junior Varsity team but they lacked a teamwork and synergy. As a coach he should make them feel like a team again and perform their best in the Championships.

How Do Minerals Affect Society Minerals - 1679 Words

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Should The Homicide Law Be Reformed - Free Essay Example

Sample details Pages: 7 Words: 2066 Downloads: 7 Date added: 2017/06/26 Category Law Essay Type Argumentative essay Level High school Did you like this example? Homicide law should be reformed as it is inappropriate for someone to be held liable for murder if they did not intend to kill. To what extent do you agree with this statement? Date authored: 23 rd August, 2014. Homicide is the collective term for both murder and manslaughter in England and Wales. Don’t waste time! Our writers will create an original "Should The Homicide Law Be Reformed" essay for you Create order Murder is a common law offence that has developed through the courts over time. The common definition of murder comes from Edward Coke who wrote, murder occurs when a person of sound body and mind unlawfully kills any human being under the Queens peace with malice aforethought. [1] This definition lays out both the actus reus and mens rea of the offence. The actus reus is uncontroversial: the killing of any human being during the Queens peace. This makes murder a result crime; liability flows from an action (or omission) of the defendant resulting in death. Controversy and academic debate surrounds the second part of the offence, namely the mens rea element. Malice aforethought has been interpreted by the courts as meaning with intent to kill or cause grievous bodily harm. It is this second interpretation of malice aforethought that brings the debate. It means a person can be convicted of the legal systems ultimate, heinous crime despite a lack of intention to kill. Lord Steyn expressed the problem eloquently in R v Powell; â€Å"in English law, a defendant may be convicted of murder who is in no ordinary sense a murderer.† [2] The proponents of change base their arguments around fair labelling, mandatory sentencing, interpretation of the current law and the contradictory results of as is. Debate only follows where there are two points of view, and despite the pitfalls of the current law on murder, there are proponents of the current system. The arguments for the current system revolve around the sanctity of life, difficulty of overcoming the evidential burden, a deterrent approach and a view of social responsibility. These differing viewpoints will be explored below in more detail. One of the major complaints about the current law is based on the idea of fair labelling. In our society it is seen as unjust to label someone inaccurately, especially when that label is one of murderer. Glanville Williams wrote, â€Å"the particulars state d in the conviction should convey the degree of the offenders moral guilt, or at least should not be positively misleading as to that guilt†¦ In any case, a man may feel a sense of injustice if the terms of the conviction do not represent his real guilt.† [3] To be labelled a murderer without holding the intention to kill would not be representative of the defendants ‘real guilt. Being convicted of murder not only results in a mandatory life sentence, but once, or if, the defendant leaves prison, the label remains. This will impact on that persons life potentially destroying his family, his career and right to a normal life after serving his sentence. Roger highlights the problem of fair labelling, â€Å"present labels of murder and manslaughter are each much too broad and lose their core meaning on account of their breadth. The law of murder at present equates the paedophile who kills his victim to ensure his silence with the man who intends to cause grievo us bodily harm because he is getting carried away in an argument, or perhaps in defending his property.†[4] Society draws a great distinction between the two individual scenarios mentioned by Roger however the label of murderer does not. When this label is present, society tends to overlook the details of the individual circumstances and takes the label on its own. Another major problem with the current law is the mandatory life sentence for murder. Many people would agree the most heinous crime deserves the most severe punishment however, as has been highlighted already, a convicted murderer has not necessarily carried out this heinous act as perceived by society. Currently, judges have no discretion with a murder conviction. Since the Murder (Abolition of Death Penalty) Act 1965 a conviction of murder carries with it the sentence of life imprisonment[5]. The precise length of the sentence varies under the guidelines derived from Coroners and Justice Act 2009 [6] ho wever this still sets the minimum sentence at 15 years for a defendant over the age of 18. This is to be contrasted with manslaughter for which the judge has absolute discretion on sentencing up to a maximum of life imprisonment. This allows for a judge to mitigate the severity of the crime through the sentence, a mechanism unavailable in murder[7]. Due to a court interpreted definition of murder, a defendant faces a mandatory life sentence instead of a much lower sentence based on the crime he truly had the mens rea for. It is this draconian approach to sentencing that makes someone held to be liable for murder when they did not intend to kill inappropriate. There are practical issues alongside legalistic ones, such as is the definition of grievous bodily harm, or serious bodily harm. If the liability for murder depends on the intention to cause this level of harm, there should be very clear and concise guidelines as to what this level of harm is. William Wilson writes ab out the obscurity of grievous bodily harm, â€Å"it is defined to mean nothing more precise than â€Å"serious† as opposed to â€Å"actual† bodily harm.†[8] This definition and guidance is not robust enough to fairly legitimise a murder charge. Further, to the abstruseness of the level of harm required, allowing grievous bodily harm to lead to a murder charge at all can result in the prosecution and conviction of a person for not only something he did not intend, but actually for something he precisely intended to avoid. There are several famous examples of this undesirable outcome such as that of kneecapping, a practice whereby the knees are targeted to punish the victim but with the precise intention of keeping them alive. Lord Goff entertained this scenario along with another of glassing. Despite the resulting death and clear intention to cause serious bodily harm with a broken glass, the jury â€Å"could not bring themselves to call him a murdererâ⠂¬  and Lord Goff sympathised with them. [9] It is the combination of the above arguments that lead people to cry out for reform of the law of homicide as it is currently inappropriate in regards to a murder charge without the intention to kill. However, there are also proponents of the current law. There is a strong argument for the law to enforce responsibility for ones actions. If one attacks another with the intention to cause them serious bodily harm, and that attack results in the death of victim, then the attacker is morally culpable for the victims death. This is a view endorsed by William Wilson and others, â€Å"I take the uncomplicated view, as the Criminal Law Commissioner has elsewhere argued, that those who intentionally attack others are morally responsible for and so fully legally accountable for the consequences of so doing whether or not such consequences were foreseen.†[10] This view depends on ones idea of the purpose of the criminal law howev er, for the law to hold society responsible for the outcome of their actions is more than acceptable for the majority. The current law also fits with the harm principle whereby, â€Å"the State is justified in criminalizing any conduct that causes harm to others†[11]. This view is compatible with sanctity of life arguments. For many in society, sanctity of life is sovereign, as shown by its inclusion in the European Convention of Human Rights[12]. This granting of the Right to Life necessitates any taking of life to be regulated tightly. This has led to problem areas in the law such as euthanasia and abortion, the laws for which are based on the law of murder. In light of high profiles decisions of the court system in these areas such as Nicklinson v Ministry of Justice [13] the time for change in the homicide area is not now. Parliament refuses to reform the law and neither do the courts. These decisions have been made in light of high volumes of political and legal argument yet the current system has won through. Changing the definition of murder could not only have a negative impact on the law of homicide, but also these other, highly emotive and controversial areas of law. The current law is not only compatible with these controversial areas but has also been affirmed at the highest level. The so called ‘GBH rule was the subject of a House of Lords decision in R v Cunningham [14] in which the rule was affirmed by the House including the then Lord Chancellor. Further, â€Å"the adjective ‘serious has not caused problems in the past, where juries have been instructed in murder cases† [15], and as such does not need to be reformed. This affirmed law is aligned with arguments for the law to act as a deterrent of social harms. The intentional causing of serious bodily harm is without doubt something society wants deterred, and having a severe punishment for this harm, not only in the law of homicide but also through the Offences Against the Person Act 1861[16], is a method of deterrence. Without the inclusion of this element in the law of homicide, not only would the deterrent for serious bodily harm be weaker, but many ‘true murderers would escape conviction for murder, thus creating a fair labelling problem, contradicting one of the arguments put forward by proponents of change. This is because it is very difficult to prove true inten t to kill. There would be many scenarios where the defendant did intend to kill the victim however this couldnt be proved due to the evidential burden. However, by using the intention to cause grievous bodily harm, a number of these defendants could be found guilty of murder. On balance there are strong arguments for homicide law to be left as is to deter violent crimes and make society responsible for their actions. However the law cannot be left simply because other areas of law are based upon them. There are many problems with the law as it is currently, particularly surrounding fair labelling, mandatory sentencing and difficulty of interpretation and implementation. These problems go right to the core of our legal system and cannot continue to go unchanged. The Law Commission has been ignored repeatedly by parliament but their worries remain and proposals could improve the current system. Homicide law should be reformed as it is inappropriate for someone to be held liab le for murder if they did not intend to kill and equality for all under the law must always be the ultimate practice. Bibliography Ashworth A and Horder J, The Principles of Criminal Law (7th edn, OUP 2013) 28 Coke E, ‘Institutes 3 Co Inst 47 Ashworth A, ‘Principles, Pragmatism and the Law Commissions Recommendations on homicide law reform [2007] Crim L R 333 Goff R, ‘The mental element in the crime of murder (1988) 104 LQR 30 Wilson W, ‘The structure of criminal homicide [2006] Crim LR 471 Williams G, ‘Convictions and Fair Labelling [1983] CLJ 85 Roger J, ‘The Law Commissions proposed restructuring of homicide (2006) 70(3) J Crim L 223 Crown Prosecution Service, ‘Sentencing Manual (CPS, Jan 2012) https://www.cps.gov.uk/legal/s_to_u/sentencing_manual/murder/ accessed 21 August 2014 R v Powell [1999] 1 AC 1 Nicklinson v Ministry of Justice [2014] UKSC 38 R v Cunningham [1982] AC 566 Offences A gainst the Persons Act 1861 Convention for the Protection of Human Rights and Fundamental Freedoms (European Convention on Human Rights, as amended) (ECHR) art 2 Criminal Justice Act 2003 Coroners and Justice Act 2009 Murder (Abolition of Death Penalty) Act 1965 [1] 3 Co Inst 47. [2] [1999] 1 AC 1, 14. [3] Glanville Williams, ‘Convictions and Fair Labelling [1983] CLJ 85, 85. [4] Jonathan Roger, ‘The Law Commissions proposed restructuring of homicide (2006) 70(3) J Crim L 223, 226. [5] Murder (Abolition of Death Penalty) Act 1965, s1. [6] Coroners and Justice Act 2009, s120. [7] Criminal Justice Act 2003, sch, paras 4-7. For further guidance see, Crown Prosecution Service, ‘Sentencing Manual (CPS, Jan 2012) https://www.cps.gov.uk/legal/s_to_u/sentencing_manual/murder/ accessed 21 August 2014. [8] William Wilson, ‘The structure of criminal homicide [2006] Crim LR 471, 475. [9] Robert Goff, ‘The mental element in the crime of murder (1988) 104 LQR 30, 48. [10] Wilson (n 8) 475. [11] Andrew Ashworth and Jeremy Horder, The Principles of Criminal Law (7th edn, OUP 2013) 28. [12] Convention for the Protection of Human Rights and Fundamental Freedoms (European Convention on Human Rights, as amended) (ECHR) art 2. [13] [2014] UKSC 38. [14] [1982] AC 566. [15] Andrew Ashworth, ‘Principles, Pragmatism and the Law Commissions Recommendations on homicide law reform [2007] Crim L R 333, 335. [16] Offences Against the Persons Act 1861, s18.

Puck and Bottom in A Midsummer Nights Dream Essay

One of William Shakespeare’s best remembered plays for its comical and ironic tone is A Midnight’s Summer Dream. There were characters designed to be humorous and that alone. Puck and Bottom behave very much alike, and have similar roles for different people. Both Puck and Bottom are comic relief characters in one way or the other. Both of them are needed for the play, because Puck’s spirits controls the whole story, which sets the tone for it and Bottoms comic relief for the audience and play. Bottom is the first fool or idiot to appear in the play. His first appearance is in Act I, scene ii, when the mechanicals got together. He is part of the groups called mechanicals, who are basically tradesmen who planned to put on a play for the†¦show more content†¦He is best known for his mischievous pranks on which he does on human beings, â€Å"mortals†. A few of these pranks are: ... You are that shrewd and knavish sprite Called Robin Goodfellow. Are not you he That frights the maidens of the villagery, Skim milk, and sometimes labor in the quern, And bootless make the breathless housewife churn, And sometime make the drink to bear no barm, Mislead night-wanderers, laughing at their harm? (ll. I. 33-39). These lines show a bit of his character, it shows that he enjoys these pranks and thus has a childish immature side to him, same goes to the person he is a fool for. Although he says these pranks are for his majesty and him alone, he seems to get more of a kick when playing these pranks on the mortals. His obedience to his majesty and his lust for pranks is the main cause for most of the problems in the story. He is the fool of fools, with that being said, his profession is to be a fool. He is also given nicknames in the play; the most memorable nickname is Robin Goodfellow. He provides the atmosphere for most of the story, and his mistakes are responsible for many of the complications that propel the other main plots, which one being the conflicting Athenian lovers. Puck does change within the play and this can be seen when he shows some responsibility in fixing the problem with true love he created between the two Athenian lovers. Pucks craving to entertain himself and his majesty as well as followingShow MoreRelatedA Midsummer Night’s Dream: Puck, Bottom, and Dichotomy in Comedy821 Words   |  3 PagesShakespeare wrote many well-received plays, A Midsummer Night’s Dream is one of the most popular by far, and its engaging love story and comedic tone are undoubtedly the biggest factors contributing to the production’s success. However, while the love square between the four young Athenians is the central plotline of the play, Shakespeare included many humorous elements that alter the story’s course drastically. 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Alzheimer’s Disease Amyloid Precursor Protein Gene Free Essays

string(51) " the synthesis of A\? \(Felician and Sandson 20\)\." Alzheimer’s disease, AD, is a distressing condition that involves the decline in cognition of the mind which results to psychotic disorder, and affective and behavioral disturbances (Bloom 9). It is a progressive central nervous system disorder and the main cause of dementia (Stavljenic-Rukavina 1). Alois Alzheimer in 1907 reported the case of a 51-year old Frankfurt woman who died in dementia (Bloom 9). We will write a custom essay sample on Alzheimer’s Disease Amyloid Precursor Protein Gene or any similar topic only for you Order Now He described the neuropathological condition of the woman with neurofibrillary tangles or NFTs and amyloid plaques or NPs (Bloom10). NPs are extracellular beta-amyloid peptide or A? Spherical deposits closely related to dendrites, reactive astrocytes, dystrophic axons, and activated microglia (Felician and Sandson 19). Thus, for several decades, collaborative efforts of experts from different scientific and medicinal endeavors were devoted for the neurological and pathophysiological characterization of this disease (Bloom 9). As such, the roles of four specified genes, as well as the mechanism of oxidative stress, tau, inflammation, hormonal changes, and inflammation on the AD’s neurodegeneration have been the central theme of scientific studies conducted on this disease (Felician and Sandson 19). As experts continuously gained insights on the mechanisms of neurodegeneration, pharmacological strategies are concurrently devised for the development of appropriate drug treatment and interventions (Felician and Sandson 19). Molecular Mechanism Early and late onset ADs are types of familial AD which are genetically heterogeneous. Familial AD is accounted for 10% of AD cases from 30-60 year old patients and ascribed to three types of genes which included APP, presenilin-1 or PSEN1 and presenilin-2 or PSEN2 (Stavljenic-Rukavina, 1). Nonetheless, the mutations in these genes also cause A? -level increase; A? is generated by proteolytic APP fragment that was also observed in the brains of AD patients (Stavljenic-Rukavina, 2). However, not all AD cases can be attributed to the three identified genes. Genes are then the most important determinant of AD development (Stavljenic-Rukavina, 2). On the other hand, there is a great chance for children with parents having history of familial AD to inherit the genetic traits and develop either early-onset or late-onset AD (Jayadev et. al. 375). As well, AD development threat in the offspring is directly related to age; the tendency of AD occurrence among children of parents with historical AD background increases as the children gain progress in their growth and development (Jayadev et. al. 375). The pathogenesis of Alzheimer’s disease, on cellular level, has been consistently observed. The pyramidal neurons are the type of cortical cells that are fundamentally deteriorated in AD pathogenesis resulting to the spread of NPs and NFTs in cortex areas (Felician and Sandson 20). Both NPs and NFTs are normally found in brain areas in the aging process but their concentrations and densities are peculiar in the case of AD (Felician and Sandson 20). Originally, NPs are found at the amygdala and concentrated in parietal association and order temporal cortex parts (Felician and Sandson 20). In the maturity of AD, NPs can also be observed in hippocampus, in other structures of mesial temporolimbic brain, and even in cortical and meningeal blood vessels (Felician and Sandson 20). Luckily, the areas for sensorimotor and visual are remained unaffected. Meanwhile, in the early stage of AD, NFTs can be found hippocampus, amygdala, and in entorhinal cortex, the association cortex has abundance of NFTs (Felician and Sandson 20). However, NFTs are not exclusively for the cases of AD, these are also detected in the several cerebral troubles like in dementia pugilistica, postencephalitic parkinsonism, and subacute sclerosing panencephalitis (Felician and Sandson 20). The formation of NPs is attributed to the A ? peptide deposition; A ? peptide types that only differ in C-terminal are common in cerebrovascular and extracellular plaques (Felician and Sandson 19). A ? peptide, made up of 39-43 amino acids, is normally generated from APP or amyloid precursor protein. In addition, the series of hydrophobic C-terminal is crucial in its solubility and amyloid formation rate (Felician and Sandson 19). As such, A ? with 40 amino acids, A ? 40, as well as A? peptide with 42 and 43 amino acids or A? 42 and A ? 43 respectively (Felician and Sandson 19). However, in vitro, the variants of A? 42 and A? 43 can easily form insoluble fibrils as compared with the A? 40 variant (Felician and Sandson 19). Furthermore, the incubation of these A? variants can immediately lead to coalescence implying the possible amyloid plaque deposition through these components. In line with this, diffuse plaques have nonfibrillary and A? soluble constituents denoting the senile plaques’ early stage (Felician and Sandson 19). Likewise, diffuse plaques have A? deposits in the absence of neuritic degeneration (Felician and Sandson 19). On the other hand, neurofibrillary tangles, comprised of abnormal bundles of intraneuronal filaments, are made up of tau microtubule-associated protein with high degree of phosphorylation (Felician and Sandson 19). The degree of phosphorylation is largely dependent on the enzymatic activities of kinases that are not yet fully understood (Felician and Sandson 19). Nevertheless, the intraneuronal abnormal filaments arrange themselves in either parallel or helical bundles in perikaryotic cytoplasm that make them in contact with the dentritic processes (Felician and Sandson 19). The amyloid precursor protein, a membrane glycoprotein, is consisted of 28 A? extracellular residues and 12 to 15 putative transmembrane residues (Felician and Sandson 20). It also occurs as 695, 751, and 770-amino acid isoform. While the 695-amino acid isoform occurs mainly in neurons, 770 and 751-amino acid forms are seen on both non-neural and neural cells along with protease inhibitor domains (Felician and Sandson 20). APPs are carried into the cell membrane by secretory vesicles and may undergo proteolytic bond breakage through the action of ? -secretase (Felician and Sandson 20). Consequently, this cleavage generates ? -APP, a soluble ectodomain and the precursor for A? peptide production through cleavage in A? domain. As the generation of soluble APP is, in vitro, ascribed with the activity of protein kinase C, uncleaved APP is inferred to take the proteolytic pathway (Felician and Sandson 20). On the other hand, APP intracerllular recycling and management are done through endocytotic or endosome-lysosome means. The endocytotic route causes proteolytic cleavages by means of ? – and ? -secratases leading to the synthesis of A? (Felician and Sandson 20). You read "Alzheimer’s Disease Amyloid Precursor Protein Gene" in category "Papers" Moreover, A? production is enhanced by intracellular calcium concentration which denoted the significance of calcium-rich proteases in A? production (Felician and Sandson 20). In vivo, APP cleavage occurs at N-terminus at the A? -region through the action of ? -secretase and at the C-terminus by means of ? -secretase activity (Mohan 1). Also, APP can take a pathway facilitated by ? -secretase at the A? -peptide domain producing soluble ? -APP (Mohan 1). Ezymes can also possibly attack APP without A? -peptide generation (Stavljenic-Rukavina, 1). Since the putative ? -secretase, under the control of kinase C, regulates the generation of soluble APP, any agents that supports this metabolism may hinder the A? production (Felician and Sandson 21). As well, A? deposition may also be lessened by drugs which inhibit APP cleavage into ? – and ? -secratases (Felician and Sandson 21). Nonetheless, agents that can impede A? coalescence would decrease its neurotoxicity effects (Felician and Sandson 21). After the formation of amyloid plaques, neurofibrillary tangles and inflammation dictates the death of neurons (Stavljenic-Rukavina 1). In relation to this, microglia and astrocytes cells of the brain are heavily affected by inflammatory process (Stavljenic-Rukavina 1). In AD patients, astrocytes are enlarged and produce prostaglandin which in turn sends signal to activate the inflammation mediated by arachidonic acid (Stavljenic-Rukavina, 1). On the other hand, microglia generates free radicals which cause neurons’ death (Stavljenic-Rukavina 1). Meanwhile, cell nutrients as well as its regulation components are transported through the microtubules in which structural properties are mainly dependent on tau protein (Stavljenic-Rukavina 1). In AD condition, the tau lessens its capability to bind with microtubules and binds with other tau protein resulting to knots of helical filaments called as neurofibrillary tangles (Stavljenic-Rukavina 1). APP Duplication is Sufficient to Cause Early Onset Alzheimer’s Dementia with Cerebral Amyloid Angiopathy Studies showed that A? encoding through APP gene expression leads to the development of Alzheimer-type dementia (Sleegers et. al. 2977). APP genetic expression results to elevated levels of A? 42, a 42-amino acid product of the proteolytic process (Sleegers et. al. 2977). Aside from the cleavage of APP into alpha, beta, and gamma secretases, high APP genetic expression results to elevated levels of A? 42 and A? deposition (Sleegers et. al. 2977). Meanwhile, it has been long known that APP level triplication in Down’s syndrome patients results to the development of Alzheimer type dementia at early stage; the APP excessive expression leads to neurodegeneration and A? deposition (Sleegers et. al. 2977). In relation to this, it was reported that families with cerebral amyloid angiopathy and early onset Alzheimer type dementia had APP genomic duplications which implied that APP over-expression, without full trisomy 21, has triggered the Alzheimer-type dementia (Sleegers et. al. 2977). In addition, Alzheimer-type dementia patients have elevated APP mRNA levels in their brains (Sleegers et. al. 2977). Further, the variation on the transcription of APP gene due to genetic factors was believed as the underpinning factor in the pathogenesis of the disease (Sleegers et. al. 2978). In fact, three APP mutations were observed on Alzheimer-type early-onset dementia patients. These mutations, as seen in vitro by means of trisomy 21, caused a two-fold elevation of in APP transcriptions (Sleegers et. al. 2978). With the aforementioned evidences on APP elevation through APP genomic mutations or duplications which resulted to the development of early onset AD, it could logically infer that A? has a crucial role in its aetiology (Sleegers et. al. 2978). Hence, for the evaluation of APP locus duplication on Alzheimer-type dementia cases, Sleegers et. al. conducted a study on Dutch population with early onset Alzheimer-type dementia patients. Material and Methods In the approval of the University of Antwerp medical ethical committee, the respondents of this research were recruited form an epidemiological study on early onset AD in several provinces of The Netherlands and in Rotterdam (Sleegers et. al. 2978). Patients with early-onset dementia diagnosis were enlisted based on the recommendation of medical experts and healthcare providers. As such, the assessment of the patients’ conditions was done in accordance with the standards of the Stroke-Alzheimer’s Disease and Related Disorders Association, and the National Institute of Neurological and Communicative Disorders (Sleegers et. al. 2978). Medical records of the patients and their respective relative with similar trait inheritance were made available for an in-depth examination. Meanwhile, for the assessment of genetic inheritance, 111 patients with ages 33 to 65 years old of which had 75 respondents with familial background of either late or early-onset of dementia and 10 of which have autosomal dominant inheritance history for several generations of their respective clans were studied (Sleegers et. al. 2978). The genomic DNA or gDNA was derived from lymphocytes and alleles of APP were measured by means of real-time polymerase chain reaction, PCR (Sleegers et. al. 2978). Also, the PrimerExpress software was utilized for the design of ? 2-microglubulin or hB2M, exon 5, 11, and 18, ubiquitin C or hUBC, ATP5J, APP, and GABPA (Sleegers et. al. 2978). As the APP alleles were normalized for hB2M and hUBC, 20 nanograms of genomic DNA were combined with the PCR and 400 nanomoles of the respective primers (Sleegers et. al. 2978). Finally, the duplication of the samples was done by means of dosage quotients or DQs calculation through six normal individuals and dementia patients. Patients with trisonomy 21 were also included as controls (Sleegers et. al. 2978). Fluorescence in situ hybridization, FISH, was utilized to determine APP genomic duplication (Sleegers et. al. 2978). FISH was performed on both interphase nuclei and metaphase chromosomes while the Epstein-Barr virus-transformed patients’ lymphoblasts were taken from the metaphase period by means of 0. 1 microgram/milliliter colcemid treatment and incubated, at 37 °C for 25 minutes, in hypotonic solution of 1 molar sodium hydroxide, 30 millimolar glycerol, 0. 8 millimolar magnesium chloride, 2 millimolar HEPES, and 1 millimolar calcium chloride (Sleegers et. al. 2978). This suspension then was used for 106 cells per milliliter as the chromosomes’ mechanical stretching was done through cyto-centrifugation. On the other hand, the Multiplex Amplicon Quantification, MAQ, was applied in the detection of APP locus duplication. MAQ was comprised of multiplex PCR amplification of the reference amplicons and targets which were tainted with fluorescent substance (Sleegers et. al. 2978). After MAQ, DNA fragment analysis, and comparison target amplicon DQ between control individuals and the patients were done (Sleegers et. al. 2979). Results and Discussion Real-time PCR APP measurements of 10 probands showed heterozygous duplication (Sleegers et. al. 2982). Based on the Dutch population sample, APP duplication along with segregation pattern and neuropathology tantamount to autosomal dominant inheritance and AD with excessive CAA were identified with APP duplication in a family (Sleegers et. al. 2982). Specifically, the genomic APP locus duplication were observed in five of the 65 family cases with early onset AD autosomal dominance while APP duplication was detected in a single out of ten family cases early-onset AD autosomal dominance (Sleegers et. al. 2982). Even though these numbers are small, the data generated from this study illuminated the significance of genomic APP locus duplication assessment when simple mutations were excluded in AD known genes (Sleegers et. al. 2982). In the 65 patients with familial AD history, a single genomic duplication was identified (Sleegers et. al. 2982). In addition, the genomic duplications among the Dutch samples have 1. 8% overall frequency and 2. 7% frequency in AD patients and family (Sleegers et. al. 2982). In contrast, duplication was failed to be detected on 36 patients with irregular early-onset AD which denoted that the duplication of de novo genomic APP is a weak cause of early-onset Alzheimer-type dementia (Sleegers et. al. 2982). Moreover, the duplication observed among the Dutch family samples has only APP which proved that genomic APP duplication, regardless of adjacent genes, has the capacity for AD and CAA mixed phenotype (Sleegers et. al. 2982). As well, duplication size differences signified the non-specific recombination substrate from the genomic attributes of APP locus; APP rather is in increased recombination region as imparted by other factors such as low transcription repeats (Sleegers et. al. 2982). Nevertheless, the mutation that affects APP expression among 4. 5% of the Dutch participants that either genomic APP duplication or APP mutation promoter carrier, are the frequent cause of Alzheimer-type dementia (Sleegers et. al. 2982). Polymorphism in the Promoter of the Human APP Gene The cleavage of APP produces A? with associated neurotoxicity; hence, genetic studies postulated that abnormal A? deposition neuropathologic AD conditions (Athan, Lee, Arriaga, Mayeux, and Tyco1793). The abnormal deposition of A? in AD patients has been ascribed to APP gene missence mutations and the proteolytic APP cleavage producing A? 42 which in turn triggers the development of early-onset AD (Athan, Lee, Arriaga, Mayeux, and Tyco1793). The most solid proof for this notion is the case on trisomy 21 wherein the duplication of APP gene results to increased A? peptide level and aggregation of such in the amyloid plaques of the brain (Athan, Lee, Arriaga, Mayeux, and Tyco1793). While the presenilin enyzymes enhance fibrillogenic APP conversion, the APOE or alipolipoprotein-E elevates A? coalescence and deposition (Athan, Lee, Arriaga, Mayeux, and Tyco1793). Since A? production is associated with APP concentration and on other factors in both A? and APP syntheses, it was hypothesized that the expression of APP gene is a determinant of AD development (Athan, Lee, Arriaga, Mayeux, and Tyco1793). Recently, a study reported the weak relation between AD inheritance and microsatellite sequence in the APP first intron and a tetranucleotide non-association with AD (Athan, Lee, Arriaga, Mayeux, and Tyco1794). Hence, to further scrutinize this issue, Athan et. al. anchored their study on APP promoter variant screening in tri-ethnic populations which included white, Caribbean Hispanic, and African-American as they intended to determine APP promoter identities. Methodology The respondents in this study were Manhattan residents of Washington Heights with ages of more than 65 years (Athan, Lee, Arriaga, Mayeux, and Tyco1794). Personal interview and medical background check, neuropsychological, physical and neurological examinations were done on the participants. In addition, individuals with questionable dementia, Parkinson disease, and other types of dementia were excluded in the study. Consequently, a total of 1,077 participants was successfully enlisted, whereas, 16% of them has family history of stroke (Athan, Lee, Arriaga, Mayeux, and Tyco1794). For genotyping, DNA from 1,013 respondents was taken as the panel of neuropsychologists and physicians established the criteria for the identification of AD patients along with the Clinical Dementia Rating Scale (Athan, Lee, Arriaga, Mayeux, and Tyco1794). The oligonucleotide primers used for APP promoter PCR amplification came from GenBank (Athan, Lee, Arriaga, Mayeux, and Tyco1794). From genomic DNAs and by means of Platinum Taq DNA Polymerase, the fragments were amplified while the product sequence was determined through dye terminators (Athan, Lee, Arriaga, Mayeux, and Tyco1794). Meanwhile, 15 microliter of the PCR products was introduced into WAVE fragment DNA analyzer (Athan, Lee, Arriaga, Mayeux, and Tyco1794). The haplotypes PCR products were individually cloned through pGL3 vector in between SacI and Bg III sites (Athan, Lee, Arriaga, Mayeux, and Tyco1794). On the other hand, U-87 MG glioma cells were cultured with the solution of Earle’s balanced salt and 2 millimolar L-glutamine with 10% fecal calf serum in EMEM medium (Athan, Lee, Arriaga, Mayeux, and Tyco1794). At 70% confluence, the cells were transferred by means of FuGene 6 reagent and pGL3 vectors were added to transfected DNA to maintain a constant concentration of about 1 microgram per plate of 35 squared millimeter (Athan, Lee, Arriaga, Mayeux, and Tyco1794). While the isotonic solution of phosphate-buffered sodium chloride was used to wash the U-87 cells, the 250 microliter Reporter Lysis Buffer was applied for cell lysis (Athan, Lee, Arriaga, Mayeux, and Tyco1794). After this, the centrifugation of the cell extract was done at 10,000 g for five minutes. From the supernatant, 20-microliter aliquot was taken and combined with 100 microliter Luciferase Assay Buffer for luciferase activity measurement (Athan, Lee, Arriaga, Mayeux, and Tyco1794). Then, with 10-20 microliters of the lysate ? -galactosidase assays were performed. This ? -galactosidase measurement was utilized for the normalization of the luciferase data (Athan, Lee, Arriaga, Mayeux, and Tyco1794). Each allele was counted and by sample proportion calculation, the frequencies were computed (Athan, Lee, Arriaga, Mayeux, and Tyco1794). For the ethic group comparison of allele frequency, chi square analysis was applied while logistic regression was utilized for APP promoter and AD polymorphisms odd-ratio calculation (Athan, Lee, Arriaga, Mayeux, and Tyco1794). As well, for each ethnic group, logistic regression was employed as the data were classified with respect to the APOE allele’s occurrence or non-occurrence as education and age discrepancies were adjusted. Finally, Hardy-Weinberg equilibrium was analyzed through chi square analysis while the ethnic comparison of APP promoter and AD polymorphisms odd-ratio calculation as their education, age, and sex were adjusted (Athan, Lee, Arriaga, Mayeux, and Tyco1794). Results and Discussion Two types of APP promoter polymorphisms were detected and identified, with respect to the starting site of the transcription, as GC at +37 and GC at -9 variants (Athan, Lee, Arriaga, Mayeux, and Tyco1797). In connection to this, +37C allele was typically observed among 18% African-American respondents while European and Caribbean-Hispanic have 3% and 10% respectively (Athan, Lee, Arriaga, Mayeux, and Tyco1797). Although +37C allele was commonly observed among AD patients, the adjustment of their socio-demographic attributes with respect to this allele produced non-significant observations (Athan, Lee, Arriaga, Mayeux, and Tyco1797). Also, -9C allele was hardly detected for disease association. On the other hand, even though the adjustment with respect to socio-demographic traits was made, still a strong link was found between APOE allele and AD (Athan, Lee, Arriaga, Mayeux, and Tyco1797). Moreover, the evaluation of both +37C and -9C allele variants in U-87 glioma cells through promoter-reporter assays has resulted to non-significant promoter activity (Athan, Lee, Arriaga, Mayeux, and Tyco1797). The early onset, less than 60 years old, of AD has been ascribed to APP, PSEN1 and PSEN2 while the late stage, greater than 65 years old, AD development has not yet fully explained by the genetic model (Waring and Rosenberg 329). The development of AD in late age stage was associated with APOE and to other reported genetic variants and alleles, however, they still insufficient to plausibly explain the mechanism involved in the AD occurrence (Waring and Rosenberg 329). Summary Alzheimer ’s disease is a progressive degeneration of the capacity of the mind for cognition thus affecting the psychological and affective attributes of the inflicted individual. Based on genome-wide study, children of parents with familial Alzheimer’s disease are more prone to inherit and develop this condition either as they take progress in their growth and development or at the senescence stage of their lives (Jayadev et. al. 375). The primary pointed culprit for this cognitive deterioration is the beta-amyloid peptide which is a part of amyloid precursor protein. APP passes through the fatty membrane of the cells and delineated in the different areas of the brain, even though, the normal function has not yet been fully known. As APP is attacked by enzymes, fragments are generated including A? -peptide with associated neurotoxicity. Sleegers et. al. in 2006 found the coincidence of cerebral amyloid angiopathy with Alzheimer’s disease in a Dutch multigenerational family. This genomic duplication was attributed solely to APP gene expression that was also observed in 65 Dutch families with early-onset of AD cases. However, APP locus duplication was not observed in 36 AD patients that signified the case of de novo mutation. On the other hand, Athan et. al. in 2002 reported the two types of APP promoter polymorphism which involved +37C and –9C alleles. Moreover, they found a strong link between AD inheritance and the apolipoprotein-E role. In this connection, the genetic traits of every individual should be scientifically scrutinized for an accurate determination and identification of the substance involved in the development of the disease in parallel with its molecular mechanisms. Works Cited Athan, Eleni S. , Lee, Joseph H. , Arriaga, Alex, Mayeux, Richard P. , and Tyco, Benjamin. â€Å"Polymorphism in the Promoter of the Human APP Gene. † Archives of Neurology 59 (2002): 1793-1799. Bloom, Elin. Genetic Studies of Alzheimer’s Disease. Acta Universitatis Upsaliensis. Uppsala, Sweden: Uppsala University, 2008. Felician, Olivier and Sandson, Thomas A. â€Å"The Neurobiology and Pharmacotherapy of Alzheimer’s Disease. † Journal of Neuropsychiatry and Clinical Neurosciences 11, 1 (1999): 19-31. Jayadev, Suman, Steinbart, Ellen J. , Chi, Yueh-Yun, Kukull, Walter A. , Schellenberg, Gerard D. and Bird, Thomas D. â€Å"Conjugal Alzheimer Disease. † Archives of Neurology 65, 3 (2008): 373-378. How to cite Alzheimer’s Disease Amyloid Precursor Protein Gene, Papers

Ferdinand Porsche Essay Thesis Example For Students

Ferdinand Porsche Essay Thesis LIFE AND ACHIEVEMENTS OF A PIONEERGerman engineer Ferdinand Porsche is certainly one of the most important figures if not the most imporant and influent-in the history of automobile making. This outstanding Teuton was born on September 3rd, 1875 in Mafferdorf, Germany. One of the most remarkable accomplishments of his carrer was that his work was not limited to one factory, but instead he worked in many of the most renowned car-making factories of the time. His life as an engineer started early, at the age of 22, when he designed an electric engine. In 1900 he was hired by a carmaker of the time, Lohner. He installed one of his engines on a Lohner and showed it in the Paris World Fair. The car was the show-stopper of the event, and later obtained positive results in several races. Other less important events happened between 1900 and 1923, when he was hired by the most important carmaker of the time, Daimler Motoren A.G. (Which in 1926 would join Benz to form Daimler-Benz A.G.) Duri ng this time, first with Daimler and then with Daimler-Benz, he became member of the board of directors, and designed the famed S (Sportlich) and SS (Super Sportlich). Prizes and university degrees did not take long to appear, and in the same year he joined Daimler, 1923, he was named Sir Ferdinand Porsche by the Italian government and recieved an Honoris Causa from the Stuttgart Technical Institute. Porsche worked in the design of Mercedes-Benz cars until 1928, when he left because of disagreements the other other chief engineer of the factory, Hans Nibel. But his last development in the factory was probably one of the most important: The curious, exotic and fast SSKL. After Porsche left Mercedes, he was soon hired to design the now extint Austria cars, and later joined another very important German auto maker, Auto Union. In this factory he designed the famous and complex 16-cylinder race cars. While working in Auto Union, he formed with his son Ferry an independent factory that had their last name, Porsche, as name. Ferry worked as design head. In another example of versatility and excellence, he won the contract for building the Volkswagen, a car that, according to the beliefs of Adolf Hitler, was going to put every German citizen on wheels. And it did. With help form the Nazi government, he started building the Volkswagen plant. Finally, the car hit showrooms on 1939, but the war postponed its full production until 1945.The Volkswagen became more then a car, it became a symbol of easy, reliable engineering and design, and broke every mass production record for a car. It is still produced today, after almost 60 years in countries like Mexico. After building cars for almost everyone interested in hiring him, Ferdinand Porsche finally put all his concentration in his own factory, located in Zuffenhausen. In 1948 and 1949 he works with his son Ferry in the design and production of his first model, the famed 356. In 1950, at the age of seventy-five and after living one of the most prolific lives (in the automotive sense), Ferdinand Porsche dies. His legacy in the automotive world is invaluable. His cars and his work with them, flawless. He is one of those people who rarely put foot on this planet. He is one of those people who have crossed the barrier that separates leyends form immortals, who will be remembered for many generations to come as a pioneer of the most important invention of the century, and maybe the millenium. Ferdinand Porsche had to be born with a car on his mind. Porsche. 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