bluuebunny/crossref_metadata_2025 huggingface dataset:
Jesus as Sovereign in the Passion according to John
Authors: Massyngbaerde Ford Josephine
Published: April 2009

This paper argues that in writing his account of the Passion of Jesus the author of the Fourth Gospel recognized the Hellenistic culture of his audience and their knowledge of the much discussed nature of true sovereignty. With this material in mind John presents Jesus as the friendly, suffering, servant sovereign who would be particularly familiar to those acquainted with Cynicism or Stoicism. For the Stoics every wise person was a sovereign. For John Jesus is a more inspiring model than any of those found in non-Christian religions: e.g., Heracles, Cleanthes, Socrates, or Odysseus.
Paul's Fictive Kinship Movement
Authors: Bossman David M.
Published: April 2009

This examination of Paul's kinship terminology focuses on Paul's perception of Jesus as Son and of those baptized into his death, thereby sharing in the fruits of his resurrection as adopted sons of God. In the fictive kinship model of God's bonds with those "in Christ," Paul eschews the notion of a kind of political messiahship that the Gospel accounts perceive for Jesus. Moreover, Paul opens his fictive family to gentiles in a way not so promoted in the Gospels. Thus, Paul's model of Jesus, based on rebirth as Son, carries with it a complex of implications that issue in the renewal of a more traditional kinship system for an extended family of Abraham. Adding gentiles to this kinship group creates in effect a movement, many of whose components continue even today.
The Social Context of Law in the Second Temple Period
Authors: Matthews Victor H.
Published: April 2009

In this study, cultural expectation, situational expedience, and adaptation to new social norms will be the guide for the examination of legal statements. It will be determined that in the post-exilic period, legal pronouncement blended with political expediency and religious zeal to shape the social context. Concerns over defensive posture within disputed regions, maintenance of protocol and recognition of the rights of posted garrisons in conquered territories (as at Elephantine), and the general sense that people who can be defined as identifiable groups and set in fixed patterns are easier to control may have separately or together driven Persian policy. The reforms imposed by Nehemiah and Ezra suggest both imperial meddling as well as cultural incursion by the advocates of Diasporic Judaism and its more rigid concept of law and ethnic identity.
Matthew 27:45-53 and the Turning of the Tide in Israel's History
Authors: Van Aarde Andries G.
Published: April 2009

Matthew considers both the fall of Jerusalem/the temple and the seeing of the coming of the Son of Man as being anticipated in the crucifixion/resurrection of Jesus. This article argues that the evangelist places these two events within his description of the history of Israel, that the events are revealed in Scripture, and that the period of the First Testament should not be viewed as concluded time. It is also argued that the so-called tension between "imminence" and "indeterminate future" must be understood from first-century Mediterraneans' perspective on time; that the key of Matthew's understanding of time is to be found in discerning what is called the turning of the tide; and, finally, that Matthew 27:45-54 is located where, within that discourse in the plot of Matthew, this "eschatological turning of time" is reported.
How A Cosmic Lamb Marries: The Image of the Wedding of the Lamb (Rev 19:7 ff.)
Authors: Malina Bruce J.
Published: April 2009

The purpose of this brief study is to explain the meaning of the phrase "marriage of the Lamb" and the significance of this marriage to signal the advent of a new heaven and a new earth. The terminology is demonstrably astronomical/astrological, and the vision fits in with the rest of the visions of John of Patmos.
When Prosperity Breeds Intergroup Hostility: The Effects of Relative Deprivation and Relative Gratification on Prejudice
Authors: Guimond Serge , Dambrun Michaël
Published: April 2009

In previous theory and research dealing with relative deprivation (RD), the role of relative gratification (RG), the opposite of RD, was relatively overlooked. Two experiments (N = 245) tested the impact of both RD and RG on prejudice toward socially significant outgroups. Experiment 1 manipulated temporal RD and RG by confronting participants to declining (RD) or improving (RG) job opportunities and found no effect of RD on prejudice but reliable effects of RG. Experiment 2 manipulated group RD and RG and found increased levels of generalized prejudice in both conditions while participants in the group RG condition showed, in addition, increased ingroup bias, greater willingness to support and act in favor of restrictive immigration policies, and higher social dominance orientation than the control group. These findings confirm the role of group RD and establish RG as an equally important, if not more central, variable in the psychology of intergroup relations.
Relationship of War-Zone Coping Strategies to Long-Term General Life Adjustment Among Vietnam Veterans: Combat Exposure as a Moderator Variable
Authors: Suvak Michael K. , Vogt Dawne S. , Savarese Vincent W. , King Lynda A. , King Daniel W.
Published: April 2009

In this study, we examined long-term general life adjustment among members of one trauma-exposed population, Vietnam veterans, using data from a nationally representative sample. Our particular concern was the relationship between coping strategies used in the war zone and the outcomes of achievement, life satisfaction, and lifetime adaptation (the latter defined in terms of the absence of psychosocial problems in core life domains) as a function of level of combat exposure. Hierarchical multiple regression analyses supported a hypothesized quadratic interaction between problem-focused coping and the outcomes of achievement and lifetime adaptation, with this form of coping most strongly related to adjustment (positively) at moderate levels of combat exposure. One aspect of emotion-focused coping, the use of wishful thinking, likewise interacted in a quadratic manner for the dependent variable of achievement, exhibiting its strongest association with adjustment (negatively) at moderate levels of combat exposure. The importance of interactions between coping and stressors, especially quadratic interactions, is emphasized.
Meeting Your Match: How Attractiveness Similarity Affects Approach Behavior in Mixed-Sex Dyads
Authors: van Straaten Ischa , Engels Rutger C. M. E. , Finkenauer Catrin , Holland Rob W.
Published: April 2009

This experimental study investigated approach behavior toward opposite-sex others of similar versus dissimilar physical attractiveness. Furthermore, it tested the moderating effects of sex. Single participants interacted with confederates of high and low attractiveness. Observers rated their behavior in terms of relational investment (i.e., behavioral efforts related to the improvement of interaction fluency, communication of positive interpersonal affect, and positive self-presentation). As expected, men displayed more relational investment behavior if their own physical attractiveness was similar to that of the confederate. For women, no effects of attractiveness similarity on relational investment behavior were found. Results are discussed in the light of positive assortative mating, preferences for physically attractive mates, and sex differences in attraction-related interpersonal behaviors.
Whose All Blacks?
Authors: Hope Wayne
Published: April 2009

From about the 1880s, an imagined sense of New Zealand-ness, mass communication, and the game of rugby took shape together. This process was primarily signified by the name, image, and exploits of the All Blacks. This article argues that global media and corporate sponsorship threatens the nationally constituted heritage of All Black rugby. But, the argument in question is not a nostalgic defence of some ‘golden age’. At given points in history, the All Black heritage was ideologically constructed and subjected to conflicting interpretations. The All Blacks have always been the template for a contested national imaginary. Now, however, the All Blacks are also the expression of a global corporate culture. In this context, the article explains how an old question takes on a new significance - to whom do the All Blacks belong?
Country music and cultural industry: mediating structures in transnational media flow
Authors: Abramson Bram Dov
Published: April 2009

As popular music genre, Americanness is one of the things country music signifies. The popular music industries are an integral component of an emerging global media environment, however. What happens to country music when it is in another country? This is a question in two parts. The first asks how local cultural practices interlock with the industrial structures through which generic conventions and taste formations can circulate transnationally. The second asks how this genre is fed back through the institutional channels which are contiguous with national borders. In the context of transnational media flow, increased attention to the role played by the national adjective - here, Canadian country music - can therefore help identify mediating structures and, in the process, point out the role of media policy in cultural industry. State policy as mediating structure is not in itself a useful thing, however. This article theorizes the nation as the site of a state apparatus whose goal is to ensure a space in which cultural producers’ relationships with institutions are not only structured but also structuring - to intervene in the plays of affect and taste which characterize culture’s production, consumption, and the circuit which binds them.
Sabotage and subterfuge: public relations, democracy and genetic engineering in New Zealand
Authors: Weaver C. Kay , Motion Judy
Published: April 2009

This article examines the public relations management of communication about genetic engineering in New Zealand. The theme is explored through an analysis of work developed by the consultancy Communication Trumps for, on the one hand, a private company involved in genetic research on fish, and, on the other hand, a government-supported public information campaign about genetic engineering. In relation to the issues management strategies employed by Communication Trumps, the article exemplifies how, by deploying tactics more commonly associated with propaganda and the engineering of consent, public relations can purposively attempt to undermine democratic processes. The article argues that through the attempted sabotage and silencing of the genetic engineering debate in New Zealand, the government, corporations, and the public relations industry combined in an effort to develop genetic engineering technologies while stifling public understanding of the implication of these technologies.
Signifying passages: the signs of change in Israeli street names
Authors: Pinchevski Amit , Torgovnik Efraim
Published: April 2009

Street names are mundane media through which the past is commemorated and introduced into the public sphere. Viewed from a semiotic perspective, street names constitute a spatial-text produced over time, capturing the political, social and cultural climates in which it is formed. In this article we propose an analysis of street names in four Israeli towns of different social, political and demographic backgrounds. The study is based on a two-stage analysis: an analysis of the local narratives and a hermeneutic reading of the street maps as spatial-texts. This is followed by a quantitative summary of street names according to categories. By studying practices of naming and renaming, and deciphering key elements in these spatial-texts, we conclude that street names reflect the changing character of the Israeli political, social and cultural orders. As such, they are indicative of shifts occurring in the social production of the Israeli collective memory.
Medical documentary: conjoined twins as a mediated spectacle
Authors: van Dijck José
Published: April 2009

The freak show, the public showing of misfits or wonders of nature, as various people have claimed, disappeared in the 20th century due to a changing mentality and growing medicalization in western society. Based on Michel Foucault’s and Guy Debord’s theories, the argument of this article is that the freak show has never disappeared but has transformed into a medicalized-mediated spectacle. Medical documentaries featuring the surgical separation of Siamese twins constitute the diachronic focus of this essay. Ever since the invention of the movie camera, spectacular surgical interventions have been the subject of medical documentaries. Starting with the films of Doctor Doyen in early 20th century France and ending with recent American public broadcast documentaries, I will analyze the cinematic, spectatorial and contextual changes in the production of medical mediated spectacle.
Globalization: some reflections from Latin America
Authors: Sutz Judith
Published: April 2009

This article focuses on globalization as a high-tech phenomenon, and from this perspective analyses its consequences for Latin America. On the one hand, key factors needed for ‘keeping on the right side’ of globalization are very weak in the region. On the other, there is some recognition that the importance of globalization might legitimize as levers for development those indigenous forces that have so far enjoyed scant recognition.
Identities: traditions and new communities
Authors: Martín-Barbero Jesús
Published: April 2009

Our societies are undergoing an identity revival which may not be thought of purely in terms of fundamentalism and intolerance. Rather, to a great extent this is a response to a globalization that is dissolving society as a community of meaning, intending to substitute for this a world comprised of markets, networks and flows of information. The resurgent identity processes - those of ethnicities, regions and gender - therefore respond to the excision of cultures from local space-time and bend to the logic of a global power that is taking refuge in a logic of communal power. However, in the face of the growing menace of particularism, we need to rethink how this is connected to universalism. Otherwise, we shall see ourselves obliged to choose either between the universalism inherited from the enlightenment, which excludes whole sections of the population or a tribal differentialism that asserts racist and xenophobic exclusion - an alternative that poses mortal dangers for democracy.
‘Bangsa Malaysia’: global sport, the city and the mediated refurbishment of local identities
Authors: Silk Michael
Published: April 2009

The article addresses the processes involved in the international restructuration of the spatial economy and of spaces of identity. Specifically, the focus is on the ways in which powerful groups used a sporting event - the 1998 Kuala Lumpur Commonwealth Games (Kuala Lumpur 98) - as part of an initiative to reshape and refurbish the ethnic core of Malaysian people in an attempt to attract a more mobile global capital. The paper draws from an ethnographic study of the conditions of practice at Kuala Lumpur 98. Analysis focuses on how political, economic, commercial and symbolic conditions shaped the media reproduction of the Games. Conclusions centre on the particularizing place commodification of Kuala Lumpur and the aesthetic illusion conjured up by cultural producers to mask the class, racialized, ethnic and gendered polarizations that characterize Malaysian culture.
Renal Cell Tumors Induced in CBA Male Mice by 1,2-Dimethylhydrazine
Authors: Turusov Vladimir S. , Chemeris Galina Yu.
Published: April 2009

Epithelial kidney tumors induced in CBA male mice by 1,2-dimethylhydrazine (DMH) were studied histochemically and immunohistochemically. A total of 48 tumors studied histologically were diagnosed as clear-cell, acidophilic, or mixed adenomas located in the renal cortex. Gamma-glutamyl transpeptidase (GGT) was strongly positive in normal proximal convoluted tubules, slightly positive in the cells of Bowman's capsule, and negative in 47 of 48 tumors examined. Antibodies against the new antigen obtained from the mouse liver oval cells, antigen A6, were also used. This antigen is negative in normal kidney proximal tubules but always positive in distal tubules and collecting ducts. It was also positive in all 47 GGT-negative tumors studied here. One tumor was GGT-positive and antigen A6-negative. Based on our data, it was concluded that the majority of renal cell adenomas induced by DMH in mice probably originate from the distal tubules or collecting ducts and not from the proximal tubules.
The Use of Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis to Detect Renal Damage in Sprague-Dawley Rats Treated with Gentamicin Sulfate
Authors: Kolaja Gerald J. , Vandermeer Donald A. , Packwood William H. , Satoh Paul S.
Published: April 2009

Renal toxicity is a common manifestation to the exposure of laboratory animals and humans to a wide range of xenobiotics. Traditional methods for evaluating renal damage by clinical chemistry such as blood urea nitrogen (BUN) and serum creatinine are not sensitive to early, mild changes. The use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to measure the molecular weight spectrum of urinary proteins allows for an evaluation of the functional changes associated with renal damage. The ability of the kidney to filter and reabsorb proteins is related to the functional ability of glomeruli and the proximal tubules. Gentamicin sulfate produces injury to the S-1 and S-2 segments of the proximal tubule in laboratory animals and humans. While severe damage to the tubules is associated with increased BUN, serum creatinine, and N-acetyl-β-glucosiminadase (NAG), mild injury is not detected by these means. The evaluation of urinary proteins by SDS-PAGE demonstrated renal toxicity at a dose of 6 mg/kg after 2 days of sc treatment. The NAG: creatinine ratio was shown to be elevated after 2 days of treatment at 63 mg/kg. The use of SDS-PAGE as described in this paper provides a sensitive method for detecting renal injury.
The Search for the Ideal Thrombolytic Agent: Maximize the Benefit and Minimize the Risk
Authors: Gardell Stephen J.
Published: April 2009

Streptokinase, acylated plasminogen streptokinase complex, and tissue-type plasminogen activator (tPA) are widely used for the treatment of acute myocardial infarction. These thrombolytic agents restore blood flow in occluded coronary arteries, salvage myocardial function, and decrease mortality. The success of thrombolytic therapy depends on the prompt and stable recanalization of the occluded blood vessel. Hemorrhagic events undermine the safety of fibrinolytic agents. Most bleeding complications occur at vascular puncture sites and can be avoided by limiting invasive procedures; however, an increased incidence of devastating intracranial bleeds is also encountered. The cause of thrombolytic-induced intracranial hemorrhage is unknown but may be due to lysis of protective hemostatic plugs. Another potential contributor to bleeding is activation of circulating plasminogen by the exogenous plasminogen activator to yield fluid-phase plasmin. Plasmin is a promiscuous proteinase that degrades many proteins that play pivotal roles in hemostasis and the integrity of the microvasculature. Tissue-type plasminogen activator activity is depressed in the absence of fibrin; hence, its use as a thrombolytic agent was anticipated to avoid the untoward consequences of plasminemia. However, the administration of pharmacologic doses of tPA can result in the activation of appreciable quantities of circulating plasminogen. In contrast to currently available thrombolytic agents, the activity of the vampire bat salivary plasminogen activator (BatPA) displays a strict requirement for the presence of fibrin. Assessment of BatPA using animal models of arterial thrombosis has demonstrated efficacy but without activation of systemic plasminogen. The avoidance of plasminemia when using BatPA as a fibrinolytic agent may circumvent bleeding complications that can compromise the safety of thrombolytic therapy.
Development and Application of In Vitro Models of Hematopoiesis to Drug Development
Authors: Deldar Ahmed , Stevens Charles E.
Published: April 2009

In vitro models of hematopoiesis are used increasingly in investigative hematopathology. Such models complement in vivo animal testing and have been shown to be predictive for hematotoxicity associated with anticancer and antiviral agents in humans. In vitro models of hematopoiesis consist of short-term cloning assays for various hematopoietic progenitor cells and long-term functional assays for the marrow hematopoietic microenvironment. In our laboratories, the cloning assays have been used as investigative tools to study the pathogenetic mechanisms of drug-induced blood disorders and as screening systems to investigate the possible hematotoxic potential of candidate drugs in various animal species. Data in support of these applications are presented in this paper.
Roles for In Vitro Myelotoxicity Tests in Preclinical Drug Development and Clinical Trial Planning
Authors: Parchment Ralph E. , Huang Mau , Erickson-Miller Connie L.
Published: April 2009

Myelosuppression is the dose-limiting side effect for most anti-cancer and many anti-human immunodeficiency virus agents, which can be quantitated with optimized colony-forming assays (granulocyte-macrophage, late erythroid, and megakaryocytic [for murine only] colony-forming units and early erythroid burst-forming units (BFUs)). When applied to new drug development, the assays are used for therapeutic index-based screening (e.g., less myelosuppressive analogues, structure-toxicity studies, new drug leads), interpreting efficacy data from xenotransplant models, and selecting the most accurate animal model for human hematopoietic toxicity. However, other types of assays may be required to identify the mechanism underlying myelosuppression. In clinical trial planning, in vitro colony-forming assays can be used to elucidate schedule dependency of myelotoxicity (which in turn provides clues about mechanism of action), to plan cytokine support, and to estimate dose-escalation effects. The inhibition of colony formation can be measured relative to a compound with known clinical myelotoxicity and schedule dependency to provide some idea of the toxicity expected at particular doses, and the degree of heterogeneity between individuals, during clinical trials. The predictive accuracy of the in vitro data has been proven by validation studies with alkylating agents.
Enzymic Pattern of Preneoplastic and Neoplastic Lesions Induced in the Kidney of CBA Mice by 1,2-Dimethylhydrazine
Authors: Ahn Young S. , Chemeris Galina Y. , Turusov Vladimir S. , Bannasch Peter
Published: April 2009

Mouse renal cell tumors (RCTs) were induced in male CBA mice by 5 subcutaneous injections of 8 mg 1,2-dimethylhydrazine (DMH)/kg body weight once a week. After a lag period of 2 yr kidneys were removed, and serial cryostat sections of the kidneys were histochemically analyzed for the following parameters: glycogen content, basophilia, and the activities of glycogen synthase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphatase (G6Pase), glucose-6-phosphate dehydrogenase (G6PDH), hexokinase (HK), pyruvate kinase (PK), lactate dehydrogenase (LDH), malic enzyme (ME), succinate dehydrogenase (SDH), alkaline phosphatase (ALPase) and γ-glutamyltranspeptidase (GGT). RCTs displayed the same histochemical profile irrespective of their size and growth pattern. In comparison with the normal kidney epithelium, the neoplastic cells exhibited elevated activities of enzymes for glycolysis (HK, PK, LDH) and the pentose phosphate pathway (G6PDH), while negative G6Pase and low SDH activity were observed in these cells. The majority of RCTs showed high PHO activity and weak staining for SYN. Activities of ALPase and GGT were negative in most of the RCTs. Markedly enlarged cells with atypical nuclei were detected in some advanced RCTs. Higher activities of glycolytic and mitochondrial enzymes and G6PDH were found in these enlarged cells than in other tumor cells. Tubular preneoplastic lesions were similar to neoplastic lesions in morphological and histochemical characteristics. The present study revealed that a markedly elevated capacity for glycolysis and the pentose phosphate pathway occurred in RCTs in mice. A similar histochemical pattern in the few preneoplastic tubular lesions observed suggests that these metabolic aberrations emerge early during carcinogenesis, but additional studies on early stages of renal carcinogenesis are needed to substantiate this assumption.
Spontaneous Adrenal and Hepatic Myelolipomas in the Common Marmoset
Authors: Kakinuma Chihaya , Harada Takuma , Watanabe Mitsutoshi , Shibutani Yasunori
Published: April 2009

Myelolipomas occurring simultaneously in the adrenal and liver were found in a 2.7-yr-old, bred female common marmoset ( Callithrix jacchus). The animal bore single adrenal and multiple hepatic myelolipomas. The adrenal myelolipoma consisted of mature adipose cells and focal collections of normal hematopoietic elements and was unencapsulated. In the liver, the myelolipomas, which were partially encapsulated, included a large amount of hematopoietic tissue and adipose cells that resembled normal bone marrow cells in various ways. Additionally, one of the multiple nodules contained several bony spicules with osteoblasts. Furthermore, there were invasive figures of hematopoietic cells, such as myeloblasts, erythroblasts, and megakaryocytes, in the hepatic sinusoids around the lesions. Thus, this case has some unusual morphological characteristics and is the first report, to our knowledge, on multiorganic myelolipomas in common marmosets.
BR96-Doxorubicin Conjugate (BMS-182248) Versus Doxorubicin: A Comparative Toxicity Assessment in Rats
Authors: Comereski Charles R. , Peden W. Michael , Davidson Thomas J. , Warner Garvin L. , Hirth Robert S. , Frantz Jerry D.
Published: April 2009

The toxicity of BMS-182248, an immunoglobulin (cBR96)-cytotoxic drug (doxorubicin) conjugate, was investigated in Sprague-Dawley rats at single intravenous doses of 508, 1,200, and 2,550 mg/m2 (conjugated doxorubicin doses of 14.7, 34.8, and 74 mg/m 2, respectively) and compared to that obtained from administration of free doxorubicin at single doses of 33.6 and 72 mg/m2 (approximately equivalent to that contained in the 1,200- and 2,550-mg/m2 doses of BMS-182248, respectively). Necropsies were conducted on day 8, upon death/moribund sacrifice, or after an approximate 3-mo observation period following completion of treatment.

Death/moribundity of all rats that received 72 mg/m2 and of 9 of 20 rats given 33.6 mg/m2 free doxorubicin were attributed primarily to delayed cardiotoxicity and glomerulonephropathy. With BMS-182248, death from glomerulonephropathy and cardiotoxicity occurred in only 4 of 20 rats given 2,550 mg/m2 (74 mg/m2 doxorubicin equivalent). No deaths or cardiotoxicity occurred in rats given 508 or 1,200 mg/m2 BMS-182248.

Additional effects noted with either drug included testicular atrophy, axonal degeneration of sciatic nerve and nerve tracts of brain and spinal cord, teeth (incisor) abnormalities, thymic atrophy, bone marrow hypocellularity, splenic lymphoid and red-pulp depletion, and increased extramedullary hematopoiesis in the spleen and liver. Also noted were altered chief cells in the stomach, vacuolation of adrenal gland and corpora lutea in the ovary, uterine and seminal vesicle atrophy, ulceration and myocyte regeneration/degeneration in the tongue, increased osteoclasts and osteoblasts in bone, and lymphoid hyperplasia of mandibular lymph node. In general, these effects were more severe in doxorubicin-treated rats.

All changes observed with BMS-182248 were considered primarily due to the effects of doxorubicin and were substantially less severe (most notably cardiotoxicity) compared to those produced by an equivalent amount of doxorubicin.
Demonstration of a Temporal Relationship Between Ethyl Acrylate-Induced Forestomach Cell Proliferation and Carcinogenicity
Authors: Ghanayem Burhan I. , Sanchez Idalia M. , Matthews H.B. , Elwell Michael R.
Published: April 2009

Ethyl acrylate (EA) is a known forestomach carcinogen in both rats and mice. Recent work in this laboratory indicated that carcinogenic doses of EA administered by gavage for 13 wk resulted in a sustained increase in forestomach epithelial hyperplasia as long as exposure to EA continued. However, hyperplasia regressed and no forestomach neoplasms were seen after a 19-mo recovery period. Current studies were designed to further investigate the time required for sustained hyperplasia to lead to neoplasia as well as the organ specificity of EA-induced cell proliferation/hyperplasia vs carcinogenicity. EA was administered at 200 mg/ kg (po) to male Fischer-344 rats, 5 days/wk. Squamous cell proliferation/hyperplasia was observed in the forestomach of all rats that received EA for 6 or 12 mo. Treatment of rats with EA for 12 mo followed by 2 mo of recovery resulted in the development of forestomach papillomas in 2 of 5 treated rats. Furthermore, animals treated for 12 mo and allowed 9 mo of recovery exhibited an increase in forestomach squamous cell carcinomas and papillomas at a combined incidence of 4 in 13. In contrast, animals treated with EA for 6 mo and allowed 2 or 15 mo of recovery exhibited a time-dependent regression of cell proliferation and did not develop forestomach neoplasms. No significant elevation in liver cell proliferation or neoplasia was seen at any time in any of the rats included in the present study, further confirming the organ specificity in the relationship between EA-induced cell proliferation and carcinogenicity. In conclusion, EA resulted in increased cell proliferation in the target organ of carcinogenicity (forestomach) but not in nontarget organs such as the liver. This work indicates that cell proliferation, sustained for a sufficient period of time, results in the development of neoplasia despite cessation of chemical administration. Furthermore, a temporal relationship exists between EA-induced epithelial cell proliferation and forestomach carcinogenicity.
Intramembranous and Endochondral Bone Changes Induced by a New Bisphosphonate (YM175) in the Beagle Dog
Authors: Nii Aisuke , Fujimoto Ryuhei , Okazaki Atsushi , Narita Kou , Miki Hisao
Published: April 2009

Oral treatment with a new bisphosphonate, YM175, for 13 wk resulted in increased bone tissue mass by both intramembranous and endochondral ossification processes in adult beagle dogs. Intramedullary bone formation due to intramembranous process was observed in dogs treated with a highly toxic dose of YM175. The newly formed woven bone trabeculae, showing immature to relatively mature figures, were present between the preexisting cancellous bone. The immature bone consisted of spindle-shaped mesenchymal cells with osteoid tissues. Many active osteoblasts surrounded the immature woven bone, while only few osteoclasts were seen on the surfaces of the new bone. Endochondral bone change was observed at the costochondral junction in all YM175-treated groups. Accumulation of unresorbed mineralized cartilage with its covering of bone at this site resulted in an increase in length of the area of primary spongiosa. Although the endochondral bone change induced by YM175 was due to a bisphosphonate-induced inhibitory effect on bone resorption, the intramedullary bone formation is unique to YM175.
Absorption, Metabolism, and Other Factors That Influence Drug Exposure in Toxicology Studies
Authors: Mayer Philip R.
Published: April 2009

Drug exposure in toxicology studies is dependent on input from the drug delivery system and elimination of the drug once absorbed. Although seemingly straightforward, absorption, metabolism, and other factors require a more complex interpretation of plasma concentrations and the resulting area under the plasma concentration versus time curve values at doses free from significant toxicity. Absorption may be saturable due to the intestinal, physiologic processes necessary for drug transfer, or intrinsic drug solubility limits may lead to a plateau in systemic plasma concentrations. Different vehicles or administration of drug with food or in the diet may be investigated in an effort to improve systemic exposure. Metabolic profiles may be examined to aid in the selection of a toxicology species more metabolically similar to humans. This will assist in providing adequate safety margins for metabolites as well as parent compound in comparison to humans. Safety assessment of drug metabolites has taken on added significance as our knowledge of metabolite pharmacokinetics in humans has increased. Correlation of free drug concentrations, determined in protein binding studies, may provide a better correlation with toxic effects than do total drug concentrations. Other factors, such as age, gender, and dosing interval need to be considered when interpreting toxicology studies.
The Effects of ZENECA ZD8731, an Angiotensin II Antagonist, on Renin Expression by Juxtaglomerular Cells in the Rat: Comparison of Protein and mRNA Expression as Detected by Immunohistochemistry and In Situ Hybridization
Authors: Doughty Susan E. , Ferrier Rod K. , Hillan Kenneth J. , Jackson David G.
Published: April 2009

Changes in the mRNA and protein expression of renin-secreting cells in the juxtaglomerular apparatus (JGA) were examined in the rat following administration of ZENECA ZD8731, an angiotensin II receptor antagonist. Doses of 0 or 90 mg/kg were administered daily by gavage for 26 wk. JGA hypertrophy was apparent in histological sections. Immunohistochemistry demonstrated an increase in the number of renin-containing cells in both the afferent arterioles and the interlobular arteries. Similarly, renin mRNA expression, demonstrated by in situ hybridization, had extended to more proximal segments of the afferent arterioles and was also present in efferent arterioles and interlobular arteries. In conclusion, JGA hypertrophy occurred as a result of antagonism of the angiotensin II receptor. Associated with JGA hypertrophy was increased expression of both renin and renin mRNA, indicative of stimulated renin synthesis caused by an exaggerated pharmacological response of renin-secreting cells to the loss of feedback inhibition by angiotensin II.
Toxicological Evaluation of u-hEGF
Authors: Maraschin Roberto , Bussi Rita , Conz Angelo , Orlando Luciana , Pirovano Raffaella , Nyska Abraham
Published: April 2009

The toxicological evaluation of urinary human epidermal growth factor (u-hEGF) included mutagenicity, single and repeated dose general toxicity, and teratogenicity studies in various animal species. The mutagenic potential of u-hEGF was tested in vitro (Ames test, chromosome aberration in human lymphocytes, unscheduled DNA synthesis in HeLa cells) and in vivo (chromosome aberration in Chinese hamster bone marrow and micronucleus test in rat bone marrow). No mutagenic or clastogenic effects were found. The acute toxicity of u-hEGF was evaluated in mice and rats, using single subcutaneous (sc) or intravenous (iv) injection of 15 mg/kg. No toxic effects were observed. Four-week iv daily administration of u-hEGF at the doses of 0.3, 0.9, and 3 mg/kg in the SD rat followed by 2 wk of compound withdrawal induced pronounced and generally dose-related effects (i.e., epithelial hyperplasia) in a wide range of tissues and organs, at all doses. However, these effects were not apparently detrimental to the general health of the rats. The repeated sc administration of u-hEGF to cynomolgus monkeys for 4 wk at the same doses as used in the rat study resulted in lethality after about 7 days of treatment in the 2 higher dose groups or after 14 days at the lowest dose. The main clinical signs observed were gastrointestinal effects, respiratory distress, sedation, marked loss of body weight, and cutaneous desquamation. At histology, hyperplasia of most epithelia was seen in all groups. In addition, atrophy of the ovarian follicles and necrosis of the uterine endometrium were noted. Changes considered secondary to physical distress were atrophy of the hemopoietic and lymphatic system and hepatic steatosis. The embryofetal toxicity and teratogenicity of u-hEGF was tested, using the iv route in the SD rat and the iv and sc routes in the New Zealand White rabbit. In both species, the compound was administered at the doses of 0, 0.3, 0.9, and 3 mg/kg/day, from day 6 to 15 of pregnancy in rats and 6-18 in rabbits. In the rat, an increase in body weight was noted in the dams and fetuses at the 2 high doses. No embryotoxic or teratogenic effects were observed. In the rabbit studies, mortality and severe clinical signs involving various systems, with marked effects on the eyes, were observed at all doses tested during the first days of treatment by both routes. From the reproductive point of view, most of the surviving treated gravid females showed only resorptions.
Spontaneous Vascular Neoplasms in Aged Sprague-Dawley Rats
Authors: Zwicker Gary M. , Eyster Randy C. , Sells Donald M. , Gass Jerome H.
Published: April 2009

Primary benign and malignant vascular neoplasms occurred spontaneously in 8 of 710 male (1.1%) and 4 of 710 female (0.6%) CrI:CD®Br strain Sprague-Dawley rats employed in two 2-yr oncogenicity studies (1,400) and as controls in a 1-yr toxicity study (20). Four of 13 neoplasms were found in the spleen; skin and kidney each had 2 neoplasms. Single vascular neoplasms were in the liver, testicle, uterus, mesenteric lymph node, and vagina. Hemangioma was more common (5 males, 2 females) than hemangiosarcoma (3 males, 2 females). Vascular neoplasms were considered the cause of death in 2 females, both with hemangiosarcomas involving the spleen or kidney. One male had 2 primary hemangiomas in separate organs. Vascular neoplasms are infrequently reported [1/82 females (1.2%), 1961; 9/880 both sexes (1.0%), 1985] in this rat strain. The incidence of vascular neoplasms of this report was higher in males (9) than in females (4), in contrast to incidences reported in the literature.
Longevity, Body Weight, and Neoplasia in Ad Libitum-Fed and Diet-Restricted C57BL6 Mice Fed NIH-31 Open Formula Diet
Authors: Blackwell Boon-Nam , Bucci Thomas J. , Hart Ronald W. , Turturro Angelo
Published: April 2009

Groups of C57BL6 mice of each sex were assigned to one of 2 dietary regimens, ad libitum (AL) or dietary restriction (DR), to study effects of food restriction on body weight, survival, and neoplasia. The AL and DR groups were subdivided into a scheduled sacrifice group for examination at 6-mo intervals, and a lifetime group to provide longevity data. Necropsies and microscopic examinations were conducted on 911 animals. In the lifetime group food consumption averaged 33.6 and 34.4 g per week by AL males and AL females, respectively; the DR counterparts were given 40% less. The diet contained 4.35 kcal/g. The average lifetime body weights were 34.8, 26.8, 22.6, and 21.6 g for AL males, AL females, DR males, and DR females, respectively, and their age at 50% survival was 27.5, 26.9, 31.7, and 33.5 mo. Maximal lifespan was increased 18% in DR males and females. Lifetime incidence of tumor-bearing mice was 89% and 86% for AL males and females, versus 64% for each sex of DR mice. Dramatic reduction occurred in female DR mice in lymphoma (9% vs 29%), pituitary neoplasms (1% vs 37%), and thyroid neoplasms (0.4% vs 8%). In males, hepatocellular tumors were reduced to 1% from 10% by DR. In contrast, the incidence of histiocytic sarcoma was increased in DR females and unaffected in DR males. Tumor onset was delayed in DR animals; 87% of all neoplasms in males and 95% in females had occurred in the AL mice by 24 mo, whereas the DR animals had only 52% and 39% of their lifetime incidence, respectively, by that age. This study provided comparative AL and DR data from C57BL6 mice examined randomly at 6-mo intervals (cross-sectional group) in parallel with data from animals in similar cohort that was unsampled and allowed to succumb naturally (longevity group). Dietary restriction reduced the lifetime percentage of tumor-bearing animals and the number of tumors per animal, and delayed the age at onset of most neoplasms.
Comparative Changes in the Liver of Female Fischer-344 Rats after Short-Term Feeding of a Semipurified or a Semisynthetic L-Amino Acid-Defined Choline-Deficient Diet
Authors: Nakae Dai , Mizumoto Yasushi , Andoh Nobuaki , Tamura Kazutoshi , Horiguchi Kohsuke , Endoh Takehiro , Kobayashi Eisaku , Tsujiuchi Toshifumi , Denda Ayumi , Lombardi Benito , Konishi Yoichi
Published: April 2009

Groups of female Fischer-344 rats were fed a semipurified choline-deficient (CD) diet, or a semisynthetic L-amino acid-defined choline-deficient (CDAA) diet, for up to 12 wk and effects of the 2 diets on the liver were compared. Steatosis was diffuse and more severe throughout in rats fed the CDAA diet than in rats fed the CD diet. Greater elevations in serum aspartate and alanine aminotransferase activities were also present in the former rats, along with higher 2-bromodeoxyuridine labeling indices in the liver. Discrete amounts of 8-hydroxyguanine were detected in liver DNA, but were not significantly different in rats fed the 2 diets, or from those present in a group of control rats killed at 0 time. Glutathione S- transferase placental form-positive focal lesions were not observed in any of the rats. The results show that the CDAA diet causes more severe degrees of steatosis and liver cell death and proliferation than the CD diet, raising the possibility that it may, in contrast to the CD diet, result in the eventual induction of hepatocellular carcinomas in female Fischer-344 rats.
Quantitative Microscopy of Hepatic Changes Induced by Phenethyl Isothiocyanate in Fischer-344 Rats Fed Either a Cereal-Based Diet or a Purified Diet
Authors: Gray Robert H. , Adam-Rodwell Gabriela , Maris Dorina , Haskins Jeffrey R. , Stoner Gary D.
Published: April 2009

Hepatic changes induced by phenethyl isothiocyanate (PEITC) in the liver of rats were determined by quantitative microscopy. Groups of male Fischer-344 rats were fed either a standard, cereal-based diet (Wayne rodent meal) or a purified diet (AIN-76A) containing PEITC at concentrations of 0.75 and 6.0 mmol/kg for 13 wk. Severe hepatic lipidosis was observed in control rats fed the purified diet. Addition of PEITC to the purified diet significantly reduced lipid content in hepatocytes. In contrast, lipid content in the liver of the rats fed the cereal-based diet containing PEITC was greater than in control rats maintained on the same diet. In addition, dose-related reductions in hepatocyte, lipid droplet, peroxisome, and mitochondrial volumes were observed in PEITC-treated rats fed the cereal-based diet. These results indicate that PEITC exerts differential effects on the liver of rats fed either the cereal-based or purified diet.
Importance of and Approaches to Quantification of Hepatocyte Apoptosis
Authors: Goldsworthy Thomas L. , Fransson-Steen Ronny , Maronpot Robert R.
Published: April 2009

Abnormal regulation of the life cycle of cells is a key feature of neoplasia. The net increase and growth of initiated cells, preneoplastic lesions, and tumors is highly dependent on rates of both cell proliferation and cell death. Studies of mechanisms involved in regulation of cell death and the development of methods to detect dying and dead cells thus appear to be as important as measurements of cell proliferation in understanding the growth of both normal, preneoplastic and neoplastic lesions. This article describes apoptosis in the mouse liver and its potential role in liver carcinogenesis. Quantitation of hepatocyte apoptosis is a emerging and evolving research area that will require evaluations as thoroughly as those performed with cell proliferation in order to understand all the variables that might influence its occurrence, measurement, and interpretations. Utilizing available data, various methodologies for identifying hepatocyte apoptosis are presented and compared, Aspects important for the quantitation of apoptosis in liver are emphasized. Accurate quantitation of apoptosis, in conjunction with proliferation measurements, is critical for investigations of the mechanisms of chemically induced carcinogenesis and the development of assays for growth alterations and can be applied to biologically based cancer models.
Magnetic Resonance Microscopy-A New Tool for the Toxicologic Pathologist
Authors: Delnomdedieu Marielle , Hedlund Laurence W. , Johnson G. Allan , Maronpot Robert R.
Published: April 2009

Parallel to its many applications in medical imaging, magnetic resonance (MR) microscopy is a potentially powerful tool in toxicologic pathology. Because of the intrinsic qualities of MR microscopy (noninvasiveness, 3-dimensionality, and slicing in any chosen plane), the scientist has a new means by which to investigate different types of lesions based on differential contrast. By choosing appropriate proton stains to probe the state of the water in tissues, organ structure and vasculature can be seen and progressive lesion development can be followed in a given animal. This paper discusses toxicologic pathology applications for MR microscopy and compares MR microscopy with conventional histopathology using a time-course study of bromobenzene-induced hepatotoxicity in rats. Hematoxylin and eosin (H&E)-stained histological sections are compared with MR microscopy images from fixed tissue blocks to demonstrate one of the applications of MR microscopy to toxicologic pathology. The results indicate that MR microscopy is as sensitive as conventional H&E staining in detecting bromobenzene-induced hepatic lesions.
Bile Acids in the Assessment of Hepatocellular Function
Authors: Thompson M.B.
Published: April 2009

Bile acids, which are synthesized in the liver from cholesterol, are important in the production of bile flow, excretion of cholesterol, and intestinal digestion and absorption of fats and fat-soluble vitamins. Increases and/or alterations in concentrations of bile acids in serum are specific and sensitive indicators of hepatobiliary disorders. Synthesis of bile acids in hepatocytes involves steps in endoplasmic reticulum, cytosol, mitochondria, and peroxisomes. Other important hepatocellular processes involving bile acids include active uptake by the basolateral membrane, intracellular transport, P-450-mediated conjugations and hydroxylations, and canalicular secretion. Hydrophobic bile acids produce hepatotoxicity in vivo and in vitro. In experimental and epidemiologic studies, some of these forms have been identified as causative agents in the development of colon and liver (experimental only) cancer. Conversely, several hydrophilic forms, primarily ursodeoxycholic acid, have demonstrated cytoprotective properties in a variety of clinical and experimental hepatobiliary diseases and disorders. Because bile acids can have dramatically different properties and effects, determination of mechanisms of action of these compounds has become an active area of research. Primary isolated hepatocytes provide an opportunity to investigate bile acid-related functions and effects in well-designed, carefully controlled studies. Short-term cultures have been used to study a variety of issues related to bile acids, including cytotoxicity, synthesis, and hepatocellular processing. With these systems, however, many functions of mature hepatocytes, including those pertaining to bile acids, can be lost when cultures are maintained for more than several days. Recent developments in culture techniques permit long-term maintenance of functionally stable, differentiated cells. Pertaining to bile acid research, these systems remain to be fully characterized but, in appropriate situations, they should provide important alternatives to in vivo studies and short-term in vitro assays.