Academic literature on the topic '220199 Applied Ethics not elsewhere classified'

Background: Reperfusion following ischemia can lead to more injuries than ischemia itself especially in diabetic patients. The aim of this study was to evaluate the effect of dexmedetomidine on ischemia-reperfusion injury (IRI) in rats with have hepatic IRI and diabetes mellitus. Methodology: Twenty-eight Wistar Albino rats were randomised into four groups as control (C), diabetic (DC), diabetic with hepatic ischemia-reperfusion injury (DIR), and diabetic but administered dexmedetomidine followed by hepatic IRI (DIRD) groups. Hepatic tissue samples were evaluated histopathologically by semiquantitative methods. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathion s-transpherase (GST), and catalase (CAT) enzyme levels were investigated in liver and kidney tissues as oxidative state parameters. Results: In Group DIR; hepatocyte degeneration, sinusoidal dilatation, pycnotic nucleus, and necrotic cells were found to be more in rat hepatic tissue; while mononuclear cell infiltration was higher in the parenchyme. MDA levels were significantly lower; but SOD levels were significantly higher in Group DIRD with regard to Group DIR. In the IRI induced diabetic rats’ hepatic and nephrotic tissues MDA levels, showing oxidative injury, were found to be lower. SOD levels, showing early antioxidant activity, were higher. Conclusion: The enzymatic findings of our study together with the hepatic histopathology indicate that dexmedetomidine has a potential role to decrease IRI. Key words: Hepatic ischemia reperfusion injury; Diabetes mellitus; Dexmedetomidine; Rat; MDA; SOD Citation: Sezen SC, Işık B, Bilge M, Arslan M, Çomu FM, Öztürk L, Kesimci E, Kavutçu M. Effect of dexmedetomidine on ischemia-reperfusion injury of liver and kidney tissues in experimental diabetes and hepatic ischemia-reperfusion injury induced rats. Anaesth Pain & Intensive Care 2016;20(2):143-149 Received: 21 November 2015; Reviewed: 10, 24 December 2015, 9, 10 June 2016; Corrected: 12 December 2015; Accepted: 10 June 2016 INTRODUCTİON Perioperative acute tissue injury induced by ischemia-reperfusion is a comman clinical event caused by reduced blood supply to the tissue being compromised during major surgery. Ischemia leads to cellular injury by depleting cellular energy deposits and resulting in accumulation of toxic metabolites. The reperfusion of tissues that have remained in ischemic conditions causes even more damage.1 Furthermore hepatic ischemia-reperfusion injury (IRI) demonstrates a strong relationship with peri-operative acute kidney injury.2 The etiology of diabetic complications is strongly associated with increased oxidative stress (OS). Diabetic patients are known to have a high risk of developing OS or IRI which results with tissue failure.3 The most important role in ischemia and reperfusion is played by free oxygen radicals.1 In diabetes, characterized by hyperglycemia, even more free oxygen radicals are produced due to oxidation of glucose and glycosylation of proteins.3 The structures which are most sensitive to free oxygen radicals in the cells are membrane lipids, proteins, nucleic acids and deoxyribonucleic acids.1 It has been reported that endogenous antioxidant enzymes [superoxide dismutase (SOD), glutathion s-transpherase (GST), catalase (CAT)] play an important role to alleviate IRI.4-8 Also some pharmacological agents have certain effects on IRI.1 The anesthetic agents influence endogenous antioxidant systems and free oxygen radical formation.9-12 Dexmedetomidine is a selective α-2 adrenoceptor agonist agent. It has been described as a useful and safe adjunct in many clinical applications. It has been found that it may increase urine output by considerably redistributing cardiac output, inhibiting vasopressin secretion and maintaining renal blood flow and glomerular filtration. Previous studies demonstrated that dexmedetomidine provides protection against renal, focal cerebral, cardiac, testicular, and tourniquet-induced IRI.13-18 Arslan et al observed that dexmedetomidine protected against lipid peroxidation and cellular membrane alterations in hepatic IRI, when given before induction of ischemia.17 Si et al18 demonstrated that dexmedetomidine treatment results in a partial but significant attenuation of renal demage induced by IRI through the inactivation of JAK/STAT signaling pathway in an in vivo model. The efficacy of the dexmedetomidine for IRI in diabetic patient is not resarched yet. The purpose of this experimental study was to evaluate the biochemical and histological effects of dexmedetomidine on hepatic IRI in diabetic rat’s hepatic and renal tissue. METHODOLOGY Animals and Experimental Protocol: This study was conducted in the Physiology Laboratory of Kirikkale University upon the consent of the Experimental Animals Ethics Committee of Kirikkale University. All of the procedures were performed according to the accepted standards of the Guide for the Care and Use of Laboratory Animals. In the study, 28 male Wistar Albino rats, weighing between 250 and 300 g, raised under the same environmental conditions, were used. The rats were kept under 20-21 oC at cycles of 12-hour daylight and 12-hour darkness and had free access to food until 2 hours before the anesthesia procedure. The animals were randomly separated into four groups, each containing 7 rats. Diabetes was induced by a single intraperitoneal injection of streptozotocin (Sigma Chemical, St. Louis, MO, USA) at a dose of 65 mg/kg body weight. The blood glucose levels were measured at 72 hrs following this injection. Rats were classified as diabetic if their fasting blood glucose (FBG) levels exceeded 250 mg/dl, and only animals with FBGs of > 250 mg/dl were included in the diabetic groups (dia­betes only, diabetes plus ischemia-reperfusion and diabetes plus dexmedetomidine-ischemia-reperfusion). The rats were kept alive 4 weeks after streptozotocin injection to allow development of chronic dia­betes before they were exposed to ischemia-reperfusion.(19) The rats were weighed before the study. Rats were anesthetized with intraperitoneal ketamine 100 mg/kg. The chest and abdomen were shaved and each animal was fixed in a supine position on the operating table. The abdomen was cleaned with 1% polyvinyl iodine and when dry, the operating field was covered with a sterile drape and median laparotomy was performed. There were four experimental groups (Group C (sham-control; n = 7), (Group DC (diabetes-sham-control; n = 7), Group DIR (diabetes-ischemia-reperfusion; n = 7), and Group DIRD (diabetes-ischemia-reperfusion-dexmedetomidine; n = 7). Sham operation was performed on the rats in Group C and Group DC. The sham operation consisted of mobilization of the hepatic pedicle only. The rats in this group were sacrificed 90 min after the procedure. Hepatic I/R injury was induced in Groups DIR and DIRD respectively with hepatic pedicle clamping using a vascular clamp as in the previous study of Arslan et al.(17) After an ischemic period of 45 min, the vascular clamp was removed. A reperfusion period was maintained for 45 min. In Group DIRD, dexmedetomidine hydrochloride 100 μg/kg, (Precedex 100 μg/2 ml, Abbott®, Abbott Laboratory, North Chicago, Illinois, USA) was administrated via intraperitoneal route 30 minutes before surgery. All the rats were given ketamine 100 mg/kg intraperitoneally and intracardiac blood samples were obtained. Preserving the tissue integrity by avoiding trauma, liver and renal biopsy samples were obtained. Biochemical Analysis: The liver and renal tissues were first washed with cold deionized water to discard blood contamination and then homogenized in a homogenizer. Measurements on cell contest require an initial preparation of the tissues. The preparation procedure may involve grinding of the tissue in a ground glass tissue blender using a rotor driven by a simple electric motor. The homogenizer as a tissue blender similar to the typical kitchen blender is used to emulsify and pulverize the tissue (Heidolph Instruments GMBH & CO KGDiax 900 Germany®) at 1000 U for about 3 min. After centrifugation at 10,000 g for about 60 min, the upper clear layer was taken. MDA levels were determined using the method of Van Ye et al,(20) based on the reaction of MDA with thiobarbituric acid (TBA). In the TBA test reaction, MDA and TBA react in acid pH to form a pink pigment with an absorption maximum at 532 nm. Arbitrary values obtained were compared with a series of standard solutions (1,1,3,3-tetraethoxypropane). Results were expressed as nmol/mg.protein. Part of the homogenate was extracted in ethanol/chloroform mixture (5/3 v/v) to discard the lipid fraction, which caused interferences in the activity measurements of T-SOD, CAT and GST activities. After centrifugation at 10.000 x g for 60 min, the upper clear layer was removed and used for the T-SOD, CAT, GST enzyme activity measurement by methods as described by Durak et al21, Aebi22 and Habig et al23 respectively. One unit of SOD activity was defined as the enzyme protein amount causing 50% inhibition in NBTH2 reduction rate and result were expressed in U/mg protein. The CAT activity method is based on the measurement of absorbance decrease due to H2O2 consumption at 240 nm. The GST activity method is based on the measurement of absorbance changes at 340 nm due to formation of GSH-CDNB complex. Histological determinations: Semiquantitative evaluation technique used by Abdel-Wahhab et al(24) was applied for interpreting the structural changes investigated in hepatic tissues of control and research groups. According to this, (-) (negative point) represents no structural change, while (+) (one positive point) represents mild, (++) (two positive points) medium and (+++) (three positive points) represents severe structural changes. Statistical analysis: The Statistical Package for the Social Sciences (SPSS, Chicago, IL, USA) 20.0 softwre was used for the statistical analysis. Variations in oxidative state parameters, and histopathological examination between study groups were assessed using the Kruskal-Wallis test. The Bonferroni-adjusted Mann-Whitney U-test was used after significant Kruskal-Wallis to determine which groups differed from the others. Results were expressed as mean ± standard deviation (Mean ± SD). Statistical significance was set at a p value < 0.05 for all analyses. RESULTS There was statistically significant difference observed between the groups with respect to findings from the histological changes in the rat liver tissue (hepatocyte degeneration, sinüsoidal dilatation, pycnotic nucleus, prenecrotic cell) determined by light microscopy according to semiquantitative evaluation techniques (p < 0.0001). In Group DIR, hepatocyte degeneration was significantly high compared to Group C, Group DC and Group DIRD (p < 0.0001, p < 0.0001, p = 0.002, respectively), (Table 1, Figure 1-4). Similarly, sinüsoidal dilatation was significantly higher in Group DIR (p < 0.0001, p = 0.004, p = 0.015, respectively). Although, pcynotic nucleus was decreased in Group DIRD, it did not make a significant difference in comparison to Group DIR (p = 0.053), (Table 1, Figure 1-4). The prenecrotic cells were significantly increased in Group DIR, with respect to Group C, Group DC and Group DIRD (p < 0.0001, p = 0.004, p < 0.0001, respectively), (Table 1, Figure 1-4). Table 1. The comparison of histological changes in rat hepatic tissue [Mean ± SD)] p**: Statistical significance was set at a p value < 0.05 for Kruskal-Wallis test *p < 0.05: When compared with Group DIR Figure 1: Light microscopic view of hepatic tissue of Group C (control). VC: vena centralis, *: sinusoids. ®: hepatocytes, k: Kupffer cells, G: glycogen granules, mc: minimal cellular changes, Hematoxilen & Eosin x 40 Figure 2: Light-microscopic view of hepatic tissue of Group DC (diabetes mellitus control) (G: Glycogen granules increased in number, (VC: vena centralis, *:sinusoids. ®:hepatocytes, k:Kupffer cells, G: glycogen granules, mc: minimal cellular changes; Hematoxylin & Eosin x 40) Figure 3: Light-microscopic view of hepatic tissue of Group DIR (Diabetes Mellitus and ischemia-reperfusion) (VC: vena centralis, (H) degenerative and hydrophic hepatocytes, (dej) vena centralis degeneration (centrolobar injury) (*): sinusoid dilatation. (←) pycnotic and hyperchromatic nuclei, MNL: mononuclear cell infiltration, (¯) congestion, K: Kupffer cell hyperplasia, (­) vacuolar degeneration (Hematoxylin & Eosin x 40) Figure 4: Light-microscopic view of hepatic tissue of Group DIRD (Diabetes Mellitus and ischemia-reperfusion together with dexmedetomidine applied group) (VC: vena centralis, (MNL) mononuclear cell infiltration, (dej) hydrophilic degeneration in hepatocytes around vena centralis, (conj) congestion, G: glycogen granules, (←) pycnotic and hyperchromatic nuclei, sinusoid dilatation (*) (Hematoxylin & Eosin x 40) Besides, in liver tissue parenchyma, MN cellular infiltration was a light microscopic finding; and showed significant changes among the groups (p < 0.0001). This was significantly higher in Group DIR, compared to Group C, DC, and DIRD (p < 0.0001, p=0.007, p = 0.007, respectively), (Table 1, Figure 1-4). The enzymatic activity of MDA, SOD and GST in hepatic tissues showed significant differences among the groups [(p = 0.019), (p = 0.034). (p = 0.008) respectively]. MDA enzyme activity was significantly incresed in Group DIR, according to Group C and Group DIRD (p = 0.011, p = 0.016, respectively), (Table 2). In Group DIR SOD enzyme activity was lower with respect to Group C and Group DIRD (p = 0.010, p = 0.038, respectively), (Table 2). The GST enzyme activity was significantly higher in Group DIR, when compared to Group C, DC and DIRD (p = 0.007, p = 0.038, p = 0.039, respectively), (Table 2). Table 2. Oxidative state parameters in rat hepatic tissue [Mean ± SD] p**: Statistical significance was set at a p value < 0.05 for Kruskal-Wallis test *p < 0.05: When compared with Group DIR The enzymatic activity of MDA, SOD in renal tissues, showed significant differences among the groups [(p < 0.0001), (p = 0.008) respectively ]. MDA enzyme activity was significantly incresed in Group DIR, according to Group C and Group DIRD (p < 0.0001, p < 0.0001, respectively). Also MDA enzyme activity level was significantly increased in Group DC, in comparison to Group C and Group DIRD (p = 0.003, p = 0.001, respectively), (Table 3). In Group DIR SOD enzyme activity was lower with respect to Group C and Group DIRD (p = 0.032, p = 0.013, respectively), (Table 3). The GST enzyme activity was significantly higher in Group DIR than the other three groups, however; CAT levels were similar among the groups (Table 3). Table 3: Oxidative state parameters in rat nephrotic tissue [Mean ± SD)] p**: Statistical significance was set at a p value < 0.05 for Kruskal-Wallis test *p < 0.05: When compared with Group DIR DISCUSSION In this study, we have reported the protective effect of dexmedetomidine in experimental hepatic and renal IRI model in the rat by investigating the MDA and SOD levels biochemically. Besides, hepatic histopathological findings also supported our report. Ischemic damage may occur with trauma, hemorrhagic shock, and some surgical interventions, mainly hepatic and renal resections. Reperfusion following ischemia results in even more injury than ischemia itself. IRI is an inflammatory response accompanied by free radical formation, leucocyte migration and activation, sinusoidal endothelial cellular damage, deteoriated microcirculation and coagulation and complement system activation.1 We also detected injury in hepatic and renal tissue caused by reperfusion following ischemia in liver. Experimental and clinical evidence indicates that OS is involved in both the pathogenesis and the complications of diabetes mellitus.25,26 Diabetes mellitus is a serious risk factor for the development of renal and cardiovascular disease. It is also related to fatty changes in the liver.27 Diabetes-related organ damage seems to be the result of multiple mechanisms. Diabetes has been associated with increased free radical reactions and oxidant tissue damage in STZ-induced diabetic rats and also in patients.26Oxidative stress has been implicated in the destruction of pancreatic β-cells28 and could largely contribute to the oxidant tissue damage associated with chronic hyperglycemia.29 A number of reports have shown that antioxidants can attenuate the complications of diabetes in patients30 and in experimental models.28,31 This study demonstrated that diabetes causes a tendency to increase the IRI. There is a lot of investigations related to the pharmacological agents or food supplements applied for decreasing OS and IRI. Antioxidant agents paly an important role in IRI by effecting antioxidant system or lessening the formation of ROS. It has been reported that anesthetic agents too, are effective in oxidative stress.1 During surgical interventions, it seems rational to get benefit from anesthetic agents in prevention of OS caused by IRI instead of using other agents. It has been declared that; dexmedetomidine; as an α-2 agonist with sedative, hypnotic properties; is important in prevention of renal, focal, cerebral, cardiac, testicular and tourniquet-induced IRI.13-18 On the other hand Bostankolu et al. concluded that dexmedetomidine did not have an additional protective role for tournique induced IRI during routine general anesthesia.32 In this study; we have shown that dexmedetomidine has a reducing effect in IRI in diabetic rats. Some biochemical tests and histopathological evaluations are applied for bringing up oxidative stress and IRI in the tissues. Reactive oxygen species (ROS) that appear with reperfusion injury damage cellular structures through the process of the lipid peroxidation of cellular membranes and yield toxic metabolites such as MDA.33 As an important intermidiate product in lipid peroxidation, MDA is used as a sensitive marker of IRI.34 ROS-induced tissue injury is triggered by various defense mechanisms.35 The first defence mechanisms include the antioxidant enzymes of SOD, CAT, and GPx. These endogenous antioxidants are the first lines of defence against oxidative stres and act by scavenging potentially damaging free radical moieties.36 There is a balance between ROS and the scavenging capacity of antioxidant enzymes.1-8 In this study, for evaluation of oxidative damage and antioxidant activity, MDS, SOD, GST and CAT levels were determined in liver and kidney tissues. MDA levels in hepatic and renal tissues were higher in Group DIR compared to Group C and Group DIRD. GST levels were higher in Group DIR compared to all the other three groups. When the groups were arranged from highest to lowest order, with respect to CAT levels, the order was; Group DIR, Group DIRD, Group DC and Group C. However, the difference was not significant. The acute phase reactant MDA, as a marker of OS, was found to be high in Group DIR and low in Group DIRD. This could be interpreted as the presence of protective effect of dexmedetomidine in IRI. IRI developing in splanchnic area causes injury also in the other organs.35 Leithead et al showed that clinically significant hepatic IRI demonstrates a strong relationship with peri-operative acute kidney injury.2 In our experimental research that showed correlation to that of research by Leithead et al. After hepatic IRI in diabetic rats renal OS marker MDA levels were significantly more in Group DIR than Group DIRD. In our study, we observed histopathological changes in the ischemic liver tissue and alterations in the level of MDA, SOD, GST and CAT levels which are OS markers. Histopathological changes of the liver tissues are hepatocyt degeneration, sinusoidal dilatation, nuclear picnosis, celluler necrosis, mononuclear cell infiltrationat paranchimal tissue. These histopathological injury scores were significantly lower in the Group DIRD than those in group DIR. LIMITATION Study limitation is there was no negative control group, as this type of surgical intervention is not possible in rats without anesthesia. CONCLUSION The enzymatic findings of our study together with the hepatic histopathology indicate that dexmedetomidine has a potential role to decrease ischemia-reperfusion injury. Conflict of interest and funding: The authors have not received any funding or benefits from industry or elsewhere to conduct this study. Author contribution: ŞCS: Concept, conduction of the study work and manuscript editing; BI: the main author to write the article; MB & MK: biochemical analysis; MA: manuscript writing; FMÇ: helped us with experimental study; LÖ & EK: collection of data REFERENCES Collard CD, Gelman S. Pathophysiology, clinical manifestations, and prevention of ischemia-reperfusion injury. Anesthesiology. 2001;94(6):1133. [PubMed] [Free full text] Leithead JA, Armstrong MJ, Corbett C, Andrew M, Kothari C, Gunson BK, et al. Hepatic ischemia reperfusion injury is associated with acute kidney injury following donation after brain death liver transplantation. Transpl Int. 2013;26(11):1116. doi: 10.1111/tri.12175. [PubMed] [Free full text] Panés J, Kurose I, Rodriguez-Vaca D, Anderson DC, Miyasaka M, Tso P, et al. Diabetes exacerbates inflammatory responses to ischemia-reperfusion. Circulation. 1996;93(1):161. [PubMed] [Free full text] Touyz RM. 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1991 An afternoon in late 1991 found me on a Sydney bus reading Brett Easton Ellis’ American Psycho (1991). A disembarking passenger paused at my side and, as I glanced up, hissed, ‘I don’t know how you can read that filth’. As she continued to make her way to the front of the vehicle, I was as stunned as if she had struck me physically. There was real vehemence in both her words and how they were delivered, and I can still see her eyes squeezing into slits as she hesitated while curling her mouth around that final angry word: ‘filth’. Now, almost fifteen years later, the memory is remarkably vivid. As the event is also still remarkable; this comment remaining the only remark ever made to me by a stranger about anything I have been reading during three decades of travelling on public transport. That inflamed commuter summed up much of the furore that greeted the publication of American Psycho. More than this, and unusually, condemnation of the work both actually preceded, and affected, its publication. Although Ellis had been paid a substantial U.S. $300,000 advance by Simon & Schuster, pre-publication stories based on circulating galley proofs were so negative—offering assessments of the book as: ‘moronic … pointless … themeless … worthless (Rosenblatt 3), ‘superficial’, ‘a tapeworm narrative’ (Sheppard 100) and ‘vile … pornography, not literature … immoral, but also artless’ (Miner 43)—that the publisher cancelled the contract (forfeiting the advance) only months before the scheduled release date. CEO of Simon & Schuster, Richard E. Snyder, explained: ‘it was an error of judgement to put our name on a book of such questionable taste’ (quoted in McDowell, “Vintage” 13). American Psycho was, instead, published by Random House/Knopf in March 1991 under its prestige paperback imprint, Vintage Contemporary (Zaller; Freccero 48) – Sonny Mehta having signed the book to Random House some two days after Simon & Schuster withdrew from its agreement with Ellis. While many commented on the fact that Ellis was paid two substantial advances, it was rarely noted that Random House was a more prestigious publisher than Simon & Schuster (Iannone 52). After its release, American Psycho was almost universally vilified and denigrated by the American critical establishment. The work was criticised on both moral and aesthetic/literary/artistic grounds; that is, in terms of both what Ellis wrote and how he wrote it. Critics found it ‘meaningless’ (Lehmann-Haupt C18), ‘abysmally written … schlock’ (Kennedy 427), ‘repulsive, a bloodbath serving no purpose save that of morbidity, titillation and sensation … pure trash, as scummy and mean as anything it depicts, a dirty book by a dirty writer’ (Yardley B1) and ‘garbage’ (Gurley Brown 21). Mark Archer found that ‘the attempt to confuse style with content is callow’ (31), while Naomi Wolf wrote that: ‘overall, reading American Psycho holds the same fascination as watching a maladjusted 11-year-old draw on his desk’ (34). John Leo’s assessment sums up the passionate intensity of those critical of the work: ‘totally hateful … violent junk … no discernible plot, no believable characterization, no sensibility at work that comes anywhere close to making art out of all the blood and torture … Ellis displays little feel for narration, words, grammar or the rhythm of language’ (23). These reviews, as those printed pre-publication, were titled in similarly unequivocal language: ‘A Revolting Development’ (Sheppard 100), ‘Marketing Cynicism and Vulgarity’ (Leo 23), ‘Designer Porn’ (Manguel 46) and ‘Essence of Trash’ (Yardley B1). Perhaps the most unambiguous in its message was Roger Rosenblatt’s ‘Snuff this Book!’ (3). Of all works published in the U.S.A. at that time, including those clearly carrying X ratings, the Los Angeles chapter of the National Organization for Women (NOW) selected American Psycho for special notice, stating that the book ‘legitimizes inhuman and savage violence masquerading as sexuality’ (NOW 114). Judging the book ‘the most misogynistic communication’ the organisation had ever encountered (NOW L.A. chapter president, Tammy Bruce, quoted in Kennedy 427) and, on the grounds that ‘violence against women in any form is no longer socially acceptable’ (McDowell, “NOW” C17), NOW called for a boycott of the entire Random House catalogue for the remainder of 1991. Naomi Wolf agreed, calling the novel ‘a violation not of obscenity standards, but of women’s civil rights, insofar as it results in conditioning male sexual response to female suffering or degradation’ (34). Later, the boycott was narrowed to Knopf and Vintage titles (Love 46), but also extended to all of the many products, companies, corporations, firms and brand names that are a feature of Ellis’s novel (Kauffman, “American” 41). There were other unexpected responses such as the Walt Disney Corporation barring Ellis from the opening of Euro Disney (Tyrnauer 101), although Ellis had already been driven from public view after receiving a number of death threats and did not undertake a book tour (Kennedy 427). Despite this, the book received significant publicity courtesy of the controversy and, although several national bookstore chains and numerous booksellers around the world refused to sell the book, more than 100,000 copies were sold in the U.S.A. in the fortnight after publication (Dwyer 55). Even this success had an unprecedented effect: when American Psycho became a bestseller, The New York Times announced that it would be removing the title from its bestseller lists because of the book’s content. In the days following publication in the U.S.A., Canadian customs announced that it was considering whether to allow the local arm of Random House to, first, import American Psycho for sale in Canada and, then, publish it in Canada (Kirchhoff, “Psycho” C1). Two weeks later, when the book was passed for sale (Kirchhoff, “Customs” C1), demonstrators protested the entrance of a shipment of the book. In May, the Canadian Defence Force made headlines when it withdrew copies of the book from the library shelves of a navy base in Halifax (Canadian Press C1). Also in May 1991, the Australian Office of Film and Literature Classification (OFLC), the federal agency that administers the classification scheme for all films, computer games and ‘submittable’ publications (including books) that are sold, hired or exhibited in Australia, announced that it had classified American Psycho as ‘Category 1 Restricted’ (W. Fraser, “Book” 5), to be sold sealed, to only those over 18 years of age. This was the first such classification of a mainstream literary work since the rating scheme was introduced (Graham), and the first time a work of literature had been restricted for sale since Philip Roth’s Portnoy’s Complaint in 1969. The chief censor, John Dickie, said the OFLC could not justify refusing the book classification (and essentially banning the work), and while ‘as a satire on yuppies it has a lot going for it’, personally he found the book ‘distasteful’ (quoted in W. Fraser, “Sensitive” 5). Moreover, while this ‘R’ classification was, and remains, a national classification, Australian States and Territories have their own sale and distribution regulation systems. Under this regime, American Psycho remains banned from sale in Queensland, as are all other books in this classification category (Vnuk). These various reactions led to a flood of articles published in the U.S.A., Canada, Australia and the U.K., voicing passionate opinions on a range of issues including free speech and censorship, the corporate control of artistic thought and practice, and cynicism on the part of authors and their publishers about what works might attract publicity and (therefore) sell in large numbers (see, for instance, Hitchens 7; Irving 1). The relationship between violence in society and its representation in the media was a common theme, with only a few commentators (including Norman Mailer in a high profile Vanity Fair article) suggesting that, instead of inciting violence, the media largely reflected, and commented upon, societal violence. Elayne Rapping, an academic in the field of Communications, proposed that the media did actively glorify violence, but only because there was a market for such representations: ‘We, as a society love violence, thrive on violence as the very basis of our social stability, our ideological belief system … The problem, after all, is not media violence but real violence’ (36, 38). Many more commentators, however, agreed with NOW, Wolf and others and charged Ellis’s work with encouraging, and even instigating, violent acts, and especially those against women, calling American Psycho ‘a kind of advertising for violence against women’ (anthropologist Elliot Leyton quoted in Dwyer 55) and, even, a ‘how-to manual on the torture and dismemberment of women’ (Leo 23). Support for the book was difficult to find in the flood of vitriol directed against it, but a small number wrote in Ellis’s defence. Sonny Mehta, himself the target of death threats for acquiring the book for Random House, stood by this assessment, and was widely quoted in his belief that American Psycho was ‘a serious book by a serious writer’ and that Ellis was ‘remarkably talented’ (Knight-Ridder L10). Publishing director of Pan Macmillan Australia, James Fraser, defended his decision to release American Psycho on the grounds that the book told important truths about society, arguing: ‘A publisher’s office is a clearing house for ideas … the real issue for community debate [is] – to what extent does it want to hear the truth about itself, about individuals within the community and about the governments the community elects. If we care about the preservation of standards, there is none higher than this. Gore Vidal was among the very few who stated outright that he liked the book, finding it ‘really rather inspired … a wonderfully comic novel’ (quoted in Tyrnauer 73). Fay Weldon agreed, judging the book as ‘brilliant’, and focusing on the importance of Ellis’s message: ‘Bret Easton Ellis is a very good writer. He gets us to a ‘T’. And we can’t stand it. It’s our problem, not his. American Psycho is a beautifully controlled, careful, important novel that revolves around its own nasty bits’ (C1). Since 1991 As unlikely as this now seems, I first read American Psycho without any awareness of the controversy raging around its publication. I had read Ellis’s earlier works, Less than Zero (1985) and The Rules of Attraction (1987) and, with my energies fully engaged elsewhere, cannot now even remember how I acquired the book. Since that angry remark on the bus, however, I have followed American Psycho’s infamy and how it has remained in the public eye over the last decade and a half. Australian OFLC decisions can be reviewed and reversed – as when Pasolini’s final film Salo (1975), which was banned in Australia from the time of its release in 1975 until it was un-banned in 1993, was then banned again in 1998 – however, American Psycho’s initial classification has remained unchanged. In July 2006, I purchased a new paperback copy in rural New South Wales. It was shrink-wrapped in plastic and labelled: ‘R. Category One. Not available to persons under 18 years. Restricted’. While exact sales figures are difficult to ascertain, by working with U.S.A., U.K. and Australian figures, this copy was, I estimate, one of some 1.5 to 1.6 million sold since publication. In the U.S.A., backlist sales remain very strong, with some 22,000 copies sold annually (Holt and Abbott), while lifetime sales in the U.K. are just under 720,000 over five paperback editions. Sales in Australia are currently estimated by Pan MacMillan to total some 100,000, with a new printing of 5,000 copies recently ordered in Australia on the strength of the book being featured on the inaugural Australian Broadcasting Commission’s First Tuesday Book Club national television program (2006). Predictably, the controversy around the publication of American Psycho is regularly revisited by those reviewing Ellis’s subsequent works. A major article in Vanity Fair on Ellis’s next book, The Informers (1994), opened with a graphic description of the death threats Ellis received upon the publication of American Psycho (Tyrnauer 70) and then outlined the controversy in detail (70-71). Those writing about Ellis’s two most recent novels, Glamorama (1999) and Lunar Park (2005), have shared this narrative strategy, which also forms at least part of the frame of every interview article. American Psycho also, again predictably, became a major topic of discussion in relation to the contracting, making and then release of the eponymous film in 2000 as, for example, in Linda S. Kauffman’s extensive and considered review of the film, which spent the first third discussing the history of the book’s publication (“American” 41-45). Playing with this interest, Ellis continues his practice of reusing characters in subsequent works. Thus, American Psycho’s Patrick Bateman, who first appeared in The Rules of Attraction as the elder brother of the main character, Sean – who, in turn, makes a brief appearance in American Psycho – also turns up in Glamorama with ‘strange stains’ on his Armani suit lapels, and again in Lunar Park. The book also continues to be regularly cited in discussions of censorship (see, for example, Dubin; Freccero) and has been included in a number of university-level courses about banned books. In these varied contexts, literary, cultural and other critics have also continued to disagree about the book’s impact upon readers, with some persisting in reading the novel as a pornographic incitement to violence. When Wade Frankum killed seven people in Sydney, many suggested a link between these murders and his consumption of X-rated videos, pornographic magazines and American Psycho (see, for example, Manne 11), although others argued against this (Wark 11). Prosecutors in the trial of Canadian murderer Paul Bernardo argued that American Psycho provided a ‘blueprint’ for Bernardo’s crimes (Canadian Press A5). Others have read Ellis’s work more positively, as for instance when Sonia Baelo Allué compares American Psycho favourably with Thomas Harris’s The Silence of the Lambs (1988) – arguing that Harris not only depicts more degrading treatment of women, but also makes Hannibal Lecter, his antihero monster, sexily attractive (7-24). Linda S. Kauffman posits that American Psycho is part of an ‘anti-aesthetic’ movement in art, whereby works that are revoltingly ugly and/or grotesque function to confront the repressed fears and desires of the audience and explore issues of identity and subjectivity (Bad Girls), while Patrick W. Shaw includes American Psycho in his work, The Modern American Novel of Violence because, in his opinion, the violence Ellis depicts is not gratuitous. Lost, however, in much of this often-impassioned debate and dialogue is the book itself – and what Ellis actually wrote. 21-years-old when Less than Zero was published, Ellis was still only 26 when American Psycho was released and his youth presented an obvious target. In 1991, Terry Teachout found ‘no moment in American Psycho where Bret Easton Ellis, who claims to be a serious artist, exhibits the workings of an adult moral imagination’ (45, 46), Brad Miner that it was ‘puerile – the very antithesis of good writing’ (43) and Carol Iannone that ‘the inclusion of the now famous offensive scenes reveals a staggering aesthetic and moral immaturity’ (54). Pagan Kennedy also ‘blamed’ the entire work on this immaturity, suggesting that instead of possessing a developed artistic sensibility, Ellis was reacting to (and, ironically, writing for the approval of) critics who had lauded the documentary realism of his violent and nihilistic teenage characters in Less than Zero, but then panned his less sensational story of campus life in The Rules of Attraction (427-428). Yet, in my opinion, there is not only a clear and coherent aesthetic vision driving Ellis’s oeuvre but, moreover, a profoundly moral imagination at work as well. This was my view upon first reading American Psycho, and part of the reason I was so shocked by that charge of filth on the bus. Once familiar with the controversy, I found this view shared by only a minority of commentators. Writing in the New Statesman & Society, Elizabeth J. Young asked: ‘Where have these people been? … Books of pornographic violence are nothing new … American Psycho outrages no contemporary taboos. Psychotic killers are everywhere’ (24). I was similarly aware that such murderers not only existed in reality, but also in many widely accessed works of literature and film – to the point where a few years later Joyce Carol Oates could suggest that the serial killer was an icon of popular culture (233). While a popular topic for writers of crime fiction and true crime narratives in both print and on film, a number of ‘serious’ literary writers – including Truman Capote, Norman Mailer, Kate Millet, Margaret Atwood and Oates herself – have also written about serial killers, and even crossed over into the widely acknowledged as ‘low-brow’ true crime genre. Many of these works (both popular or more literary) are vivid and powerful and have, as American Psycho, taken a strong moral position towards their subject matter. Moreover, many books and films have far more disturbing content than American Psycho, yet have caused no such uproar (Young and Caveney 120). By now, the plot of American Psycho is well known, although the structure of the book, noted by Weldon above (C1), is rarely analysed or even commented upon. First person narrator, Patrick Bateman, a young, handsome stockbroker and stereotypical 1980s yuppie, is also a serial killer. The book is largely, and innovatively, structured around this seeming incompatibility – challenging readers’ expectations that such a depraved criminal can be a wealthy white professional – while vividly contrasting the banal, and meticulously detailed, emptiness of Bateman’s life as a New York über-consumer with the scenes where he humiliates, rapes, tortures, murders, mutilates, dismembers and cannibalises his victims. Although only comprising some 16 out of 399 pages in my Picador edition, these violent scenes are extreme and certainly make the work as a whole disgustingly confronting. But that is the entire point of Ellis’s work. Bateman’s violence is rendered so explicitly because its principal role in the novel is to be inescapably horrific. As noted by Baelo Allué, there is no shift in tone between the most banally described detail and the description of violence (17): ‘I’ve situated the body in front of the new Toshiba television set and in the VCR is an old tape and appearing on the screen is the last girl I filmed. I’m wearing a Joseph Abboud suit, a tie by Paul Stuart, shoes by J. Crew, a vest by someone Italian and I’m kneeling on the floor beside a corpse, eating the girl’s brain, gobbling it down, spreading Grey Poupon over hunks of the pink, fleshy meat’ (Ellis 328). In complete opposition to how pornography functions, Ellis leaves no room for the possible enjoyment of such a scene. Instead of revelling in the ‘spine chilling’ pleasures of classic horror narratives, there is only the real horror of imagining such an act. The effect, as Kauffman has observed is, rather than arousing, often so disgusting as to be emetic (Bad Girls 249). Ellis was surprised that his detractors did not understand that he was trying to be shocking, not offensive (Love 49), or that his overall aim was to symbolise ‘how desensitised our culture has become towards violence’ (quoted in Dwyer 55). Ellis was also understandably frustrated with readings that conflated not only the contents of the book and their meaning, but also the narrator and author: ‘The acts described in the book are truly, indisputably vile. The book itself is not. Patrick Bateman is a monster. I am not’ (quoted in Love 49). Like Fay Weldon, Norman Mailer understood that American Psycho posited ‘that the eighties were spiritually disgusting and the author’s presentation is the crystallization of such horror’ (129). Unlike Weldon, however, Mailer shied away from defending the novel by judging Ellis not accomplished enough a writer to achieve his ‘monstrous’ aims (182), failing because he did not situate Bateman within a moral universe, that is, ‘by having a murderer with enough inner life for us to comprehend him’ (182). Yet, the morality of Ellis’s project is evident. By viewing the world through the lens of a psychotic killer who, in many ways, personifies the American Dream – wealthy, powerful, intelligent, handsome, energetic and successful – and, yet, who gains no pleasure, satisfaction, coherent identity or sense of life’s meaning from his endless, selfish consumption, Ellis exposes the emptiness of both that world and that dream. As Bateman himself explains: ‘Surface, surface, surface was all that anyone found meaning in. This was civilisation as I saw it, colossal and jagged’ (Ellis 375). Ellis thus situates the responsibility for Bateman’s violence not in his individual moral vacuity, but in the barren values of the society that has shaped him – a selfish society that, in Ellis’s opinion, refused to address the most important issues of the day: corporate greed, mindless consumerism, poverty, homelessness and the prevalence of violent crime. Instead of pornographic, therefore, American Psycho is a profoundly political text: Ellis was never attempting to glorify or incite violence against anyone, but rather to expose the effects of apathy to these broad social problems, including the very kinds of violence the most vocal critics feared the book would engender. Fifteen years after the publication of American Psycho, although our societies are apparently growing in overall prosperity, the gap between rich and poor also continues to grow, more are permanently homeless, violence – whether domestic, random or institutionally-sanctioned – escalates, and yet general apathy has intensified to the point where even the ‘ethics’ of torture as government policy can be posited as a subject for rational debate. The real filth of the saga of American Psycho is, thus, how Ellis’s message was wilfully ignored. While critics and public intellectuals discussed the work at length in almost every prominent publication available, few attempted to think in any depth about what Ellis actually wrote about, or to use their powerful positions to raise any serious debate about the concerns he voiced. Some recent critical reappraisals have begun to appreciate how American Psycho is an ‘ethical denunciation, where the reader cannot but face the real horror behind the serial killer phenomenon’ (Baelo Allué 8), but Ellis, I believe, goes further, exposing the truly filthy causes that underlie the existence of such seemingly ‘senseless’ murder. But, Wait, There’s More It is ironic that American Psycho has, itself, generated a mini-industry of products. A decade after publication, a Canadian team – filmmaker Mary Harron, director of I Shot Andy Warhol (1996), working with scriptwriter, Guinevere Turner, and Vancouver-based Lions Gate Entertainment – adapted the book for a major film (Johnson). Starring Christian Bale, Chloë Sevigny, Willem Dafoe and Reese Witherspoon and, with an estimated budget of U.S.$8 million, the film made U.S.$15 million at the American box office. The soundtrack was released for the film’s opening, with video and DVDs to follow and the ‘Killer Collector’s Edition’ DVD – closed-captioned, in widescreen with surround sound – released in June 2005. Amazon.com lists four movie posters (including a Japanese language version) and, most unexpected of all, a series of film tie-in action dolls. The two most popular of these, judging by E-Bay, are the ‘Cult Classics Series 1: Patrick Bateman’ figure which, attired in a smart suit, comes with essential accoutrements of walkman with headphones, briefcase, Wall Street Journal, video tape and recorder, knife, cleaver, axe, nail gun, severed hand and a display base; and the 18” tall ‘motion activated sound’ edition – a larger version of the same doll with fewer accessories, but which plays sound bites from the movie. Thanks to Stephen Harris and Suzie Gibson (UNE) for stimulating conversations about this book, Stephen Harris for information about the recent Australian reprint of American Psycho and Mark Seebeck (Pan Macmillan) for sales information. References Archer, Mark. “The Funeral Baked Meats.” The Spectator 27 April 1991: 31. Australian Broadcasting Corporation. First Tuesday Book Club. First broadcast 1 August 2006. Baelo Allué, Sonia. “The Aesthetics of Serial Killing: Working against Ethics in The Silence of the Lambs (1988) and American Psycho (1991).” Atlantis 24.2 (Dec. 2002): 7-24. Canadian Press. “Navy Yanks American Psycho.” The Globe and Mail 17 May 1991: C1. Canadian Press. “Gruesome Novel Was Bedside Reading.” Kitchener-Waterloo Record 1 Sep. 1995: A5. Dubin, Steven C. “Art’s Enemies: Censors to the Right of Me, Censors to the Left of Me.” Journal of Aesthetic Education 28.4 (Winter 1994): 44-54. Dwyer, Victor. “Literary Firestorm: Canada Customs Scrutinizes a Brutal Novel.” Maclean’s April 1991: 55. Ellis, Bret Easton. American Psycho. London: Macmillan-Picador, 1991. ———. Glamorama. New York: Knopf, 1999. ———. The Informers. New York: Knopf, 1994. ———. Less than Zero. New York: Simon & Schuster, 1985. ———. Lunar Park. New York: Knopf, 2005. ———. The Rules of Attraction. New York: Simon & Schuster, 1987. Fraser, James. :The Case for Publishing.” The Bulletin 18 June 1991. Fraser, William. “Book May Go under Wraps.” The Sydney Morning Herald 23 May 1991: 5. ———. “The Sensitive Censor and the Psycho.” The Sydney Morning Herald 24 May 1991: 5. Freccero, Carla. “Historical Violence, Censorship, and the Serial Killer: The Case of American Psycho.” Diacritics: A Review of Contemporary Criticism 27.2 (Summer 1997): 44-58. Graham, I. “Australian Censorship History.” Libertus.net 9 Dec. 2001. 17 May 2006 http://libertus.net/censor/hist20on.html>. Gurley Brown, Helen. Commentary in “Editorial Judgement or Censorship?: The Case of American Psycho.” The Writer May 1991: 20-23. Harris, Thomas. The Silence of the Lambs. New York: St Martins Press, 1988. Harron, Mary (dir.). American Psycho [film]. Edward R. Pressman Film Corporation, Lions Gate Films, Muse Productions, P.P.S. Films, Quadra Entertainment, Universal Pictures, 2004. Hitchens, Christopher. “Minority Report.” The Nation 7-14 January 1991: 7. Holt, Karen, and Charlotte Abbott. “Lunar Park: The Novel.” Publishers Weekly 11 July 2005. 13 Aug. 2006 http://www.publishersweekly.com/article/CA624404.html? pubdate=7%2F11%2F2005&display=archive>. Iannone, Carol. “PC & the Ellis Affair.” Commentary Magazine July 1991: 52-4. Irving, John. “Pornography and the New Puritans.” The New York Times Book Review 29 March 1992: Section 7, 1. 13 Aug. 2006 http://www.nytimes.com/books/97/06/15/lifetimes/25665.html>. Johnson, Brian D. “Canadian Cool Meets American Psycho.” Maclean’s 10 April 2000. 13 Aug. 2006 http://www.macleans.ca/culture/films/article.jsp?content=33146>. Kauffman, Linda S. “American Psycho [film review].” Film Quarterly 54.2 (Winter 2000-2001): 41-45. ———. Bad Girls and Sick Boys: Fantasies in Contemporary Art and Culture. Berkeley: University of California Press, 1998. Kennedy, Pagan. “Generation Gaffe: American Psycho.” The Nation 1 April 1991: 426-8. Kirchhoff, H. J. “Customs Clears Psycho: Booksellers’ Reaction Mixed.” The Globe and Mail 26 March 1991: C1. ———. “Psycho Sits in Limbo: Publisher Awaits Customs Ruling.” The Globe and Mail 14 March 1991: C1. Knight-Ridder News Service. “Vintage Picks up Ellis’ American Psycho.” Los Angeles Daily News 17 November 1990: L10. Lehmann-Haupt, Christopher. “Psycho: Wither Death without Life?” The New York Times 11 March 1991: C18. Leo, John. “Marketing Cynicism and Vulgarity.” U.S. News & World Report 3 Dec. 1990: 23. Love, Robert. “Psycho Analysis: Interview with Bret Easton Ellis.” Rolling Stone 4 April 1991: 45-46, 49-51. Mailer, Norman. “Children of the Pied Piper: Mailer on American Psycho.” Vanity Fair March 1991: 124-9, 182-3. Manguel, Alberto. “Designer Porn.” Saturday Night 106.6 (July 1991): 46-8. Manne, Robert. “Liberals Deny the Video Link.” The Australian 6 Jan. 1997: 11. McDowell, Edwin. “NOW Chapter Seeks Boycott of ‘Psycho’ Novel.” The New York Times 6 Dec. 1990: C17. ———. “Vintage Buys Violent Book Dropped by Simon & Schuster.” The New York Times 17 Nov. 1990: 13. Miner, Brad. “Random Notes.” National Review 31 Dec. 1990: 43. National Organization for Women. Library Journal 2.91 (1991): 114. Oates, Joyce Carol. “Three American Gothics.” Where I’ve Been, and Where I’m Going: Essays, Reviews and Prose. New York: Plume, 1999. 232-43. Rapping, Elayne. “The Uses of Violence.” Progressive 55 (1991): 36-8. Rosenblatt, Roger. “Snuff this Book!: Will Brett Easton Ellis Get Away with Murder?” New York Times Book Review 16 Dec. 1990: 3, 16. Roth, Philip. Portnoy’s Complaint. New York: Random House, 1969. Shaw, Patrick W. The Modern American Novel of Violence. Troy, NY: Whitson, 2000. Sheppard, R. Z. “A Revolting Development.” Time 29 Oct. 1990: 100. Teachout, Terry. “Applied Deconstruction.” National Review 24 June 1991: 45-6. Tyrnauer, Matthew. “Who’s Afraid of Bret Easton Ellis?” Vanity Fair 57.8 (Aug. 1994): 70-3, 100-1. Vnuk, Helen. “X-rated? Outdated.” The Age 21 Sep. 2003. 17 May 2006 http://www.theage.com.au/articles/2003/09/19/1063625202157.html>. Wark, McKenzie. “Video Link Is a Distorted View.” The Australian 8 Jan. 1997: 11. Weldon, Fay. “Now You’re Squeamish?: In a World as Sick as Ours, It’s Silly to Target American Psycho.” The Washington Post 28 April 1991: C1. Wolf, Naomi. “The Animals Speak.” New Statesman & Society 12 April 1991: 33-4. Yardley, Jonathan. “American Psycho: Essence of Trash.” The Washington Post 27 Feb. 1991: B1. Young, Elizabeth J. “Psycho Killers. Last Lines: How to Shock the English.” New Statesman & Society 5 April 1991: 24. Young, Elizabeth J., and Graham Caveney. Shopping in Space: Essays on American ‘Blank Generation’ Fiction. London: Serpent’s Tail, 1992. Zaller, Robert “American Psycho, American Censorship and the Dahmer Case.” Revue Francaise d’Etudes Americaines 16.56 (1993): 317-25. Citation reference for this article MLA Style Brien, Donna Lee. "The Real Filth in : A Critical Reassessment." M/C Journal 9.5 (2006). echo date('d M. Y'); ?> <http://journal.media-culture.org.au/0610/01-brien.php>. APA Style Brien, D. (Nov. 2006) "The Real Filth in American Psycho: A Critical Reassessment," M/C Journal, 9(5). Retrieved echo date('d M. Y'); ?> from <http://journal.media-culture.org.au/0610/01-brien.php>.

The thesis proposes and defends a maxim which can serve as a foundation and guideline for professional ethics in nursing, the maxim that nurses should act so far as possible to promote patient's self-determination. The thesis is informed by philosophical ethics and by knowledge of professional nursing practice.

Video game studies pertaining to representations of gender, race, culture, and sexuality are commonly discussed in relation to the characters, narrative, or gameplay mechanics. Video game environments are often left out of these discussions as most publications focus on how the environment was created and environmental storytelling. In this pilot study the researcher had participants analyze and discuss three futuristic, dystopian environments that contained alternative ways of representing gender, race, culture, and sexuality. The environments did not have gameplay or character interactions so that the player could focus on the environment. Results indicated that futuristic dystopian environments do not need to rely on stereotypes and harmful depictions to evoke core themes, even if they relate to violence, sex, oppression, or addiction. However, a lack of representation or a “neutral” take on representating gender, race, sexuality, and culture results in world that feels bland, isolated, and unnatural. Additionally, while participants disagreed on certain representations or noticed different aspects of the environments, the researcher found that focusing on “playtesting” just the environment can reveal how certain values, themes, and representations arise out of prop repetition, prop juxtaposition, and even how the player moves physically through the space.

An account of the nature of courage and how it figures in management decisions is developed on the basis of classical and contemporary literature in philosophy and management. The account contains seven elements, including obstacles and tools and a requirement for acting for good. The account is subject to a reality check using content analysis of articles in the business press in Australia, United Kingdom, United States and Hong Kong.