bluuebunny/crossref_metadata_2025 huggingface dataset:
What Is Catholic about Catholic Biblical Scholarship?—Revisited
Authors: Murphy Roland E.
Published: April 2009

In reply to the question, the writer claims that historical criticism can arrive at a responsible theological and "spiritual" sense of the biblical text, in harmony with the living tradition within which the exegete works. Allowing for tensions between the Testaments, the exegete must respect the integrity of both. On the personal and pastoral level, the open-ended character of the text, recognized by historical criticism, lends itself to an actualization that is vital for the ongoing life of the Bible among the people of God. This article has preserved the informality of the address given originally at the sixty-first annual meeting of the Catholic Biblical Association at the University of Scranton, August 9, 1998. The author is grateful to Michael P. O'Connor for a critical reading and suggestions on the first draft of the paper.
The Synagogue of Satan Accusation in Revelation 2:9
Authors: Bredin Mark R. J.
Published: April 2009

The accusation that the synagogue was a synagogue, not of Judeans but of Satan is connected with an internal dispute on how one faithful to Israelite traditions should live with the Roman economic system. The author of Revelation was arguing that there should be no compromise with Rome, and those who did compromise were not fit to be called Judean. The Synagogue, on the other hand, argued that peaceful coexistence with Rome was possible. It is suggested that the synagogue accused members of the church in Smyrna of not being Judean because they refused to pay the special Judean tax that allowed them to practice their religion unmolested. For the author of Revelation, however, to pay the tax would be an act of apostasy, as the tax paid for the rebuilding of the Capitoline temple.
Family and Work: Implications of Adult Attachment Styles
Authors: Vasquez Kristin , Durik Amanda M. , Hyde Janet Shibley
Published: April 2009

This study examined the role of adult attachment style in meeting the challenges of both work and family roles for parents of young children. Theory suggests that secure attachment provides a basis for successful negotiation of issues of intimacy and exploration—for adults, family, and work. Using a large sample of adults in committed relationships, studied longitudinally, we assessed satisfaction with work, satisfaction with family, stress, and role overload. Results indicated that most parents, particularly those with secure attachment styles, are able to function in multiple domains successfully. However, women and men with fearful attachment styles, characterized by views that the self is unlovable and others are untrustworthy, have marked difficulty in many family domains and some work domains. Functioning of parents with dismissing and preoccupied attachment styles fell between that of secure and fearful.
The principle of publicity, public use of reason and social control
Authors: Splichal Slavko
Published: April 2009

This article examines the intellectual history of the concept of ‘publicity’, originally defined by Immanuel Kant as the transcendental formula of public justice and the principle of the public use of reason, but later largely subsumed under the concept of ‘freedom of the press’. The notion of the press as the Fourth Estate/Power was a valid concept and legitimate form of the institutionalization of the principle of publicity in the period when newspapers emanated from a new (bourgeois) estate or class: they had a different source of legitimacy than the three classic powers, and developed as a critical impulse against the old ruling estates. Yet the discrimination in favor of the power/control function of the press, which relates to the need of ‘distrustful surveillance’ defended by Bentham, clearly abstracted freedom of the press from the Kantian quest for the public use of reason. In democratic societies where the people rather than different estates legitimize all the powers, the control dimension of publicity embodied in the corporate freedom of the press should be effectively supplemented by actions toward equalizing private citizens in the public use of reason.
A machine-like new medium - theoretical examination of interactive TV
Authors: Kim Pyungho , Sawhney Harmeet
Published: April 2009

The tension underlying interactive television (TV) systems stems from the clash between interactivity as a communication model and TV as an organizing platform. Conventional TV is a communication system with an information-producing-and-distributing center and an information-receiving periphery. Interactive communication, on the other hand, is a catalyst for a power shift away from the center as the media are reorganized into two-way communication systems. The telecommunications firms, however, organize interactive TV following the conventional TV model because it is a historically familiar and successful economic model and an exemplary control mechanism for the production, distribution, and consumption of information. Thereby interactivity in interactive TV is reduced to mechanical query-response/request-delivery processes. Since interactive TV does not unleash the new liberties of communicative action offered by new technologies, the supposedly new medium is not really a new medium.
Escraches: demonstrations, communication and political memory in post-dictatorial Argentina
Authors: Kaiser Susana
Published: April 2009

This article examines Escraches, a new form of political demonstration in post-dictatorial Argentina where hundreds of torturers and assassins, responsible for the torture and disappearance of 30,000 people, have benefited from amnesty laws. The lack of truth and accountability has had social and cultural consequences. The demonstrations, which challenge legalized impunity, engage with contemporary issues of memory and communication concerning the ‘Dirty War’ of 1976-83. The research focuses particularly on public sphere reactions to these communication strategies among young people with no direct personal memory of the violent repression that took place. The analysis is based on empirical data collected during 1998 through extensive interviews with young people from Buenos Aires.
Netscapes of power: convergence, consolidation and power in the Canadian mediascape
Authors: Winseck Dwayne
Published: April 2009

Grounded in a study of the Canadian mediascape, this article argues that trends toward media ownership consolidation are having a fundamental impact on broadcasting and the evolution of cyberspace as a whole. I argue that current trends reflect the rise of what we can call ‘Machiavellian media’ - communication and information systems saddled with three tasks: building the information society; populating cyberspace with workers/citizens/users; and projecting the ‘brand image’ of nation-states on a global plane. The article critiques the notion that new media, especially the internet, are disruptive technologies. Among other things, cyberspace is a class-divided space. More than this, though, networks - the basis of many ‘new media’ - are powerful entities and those who control them influence content providers’ access to people and people’s access to content. The article also analyzes three other factors that are affecting the evolution of networks and cyberspace: attempts to design ‘netscapes of power’, the privatization of cyberlaw, and ‘walled garden’ strategies. Together, these strategies seek to change the Internet into a mainly ‘read-only’ medium and to cybernetically integrate audiences, content and all organizational resources into a self-referentially enclosed information system governed by multimedia conglomerates’ need to defend their investments in a model of media evolution that has, at best, weak cultural foundations.
Social tagging, online communication, and Peircean semiotics: a conceptual framework
Authors: Huang Andrea Wei-Ching , Chuang Tyng-Ruey
Published: April 2009

One of the recent web developments has focused on the opportunities it presents for social tagging through user participation and collaboration. As a result, social tagging has changed the traditional online communication process. The interpretation of tagging between humans and machines may create new problems if essential questions about how social tagging corresponds to online communications, what objects the tags refer to, who the interpreters are, and why they are engaged are not explored systematically. Since such reasoning is an interpretation of social tagging among humans, tags and machines, it is a complex issue that calls for deep reflection. In this paper, we investigate the relevance of the potential problems raised by social tagging through the framework of C.S. Peirce's semiotics. We find that general phenomena of social tagging can be well classified by Peirce's 10 classes of signs for reasoning. This suggests that regarding social tagging as a sign and systematically analyzing the interpretation are positively associated with the 10 classes of signs. Peircean semiotics can be used to examine the dynamics and determinants of tagging; hence, the various uses of this categorization schema may have implications for the design and development of information systems and web applications.
Receiving the French: a bibliometric snapshot of the impact of `French theory' on information studies
Authors: Cronin Blaise , Meho Lokman I.
Published: April 2009

This study explores the extent to which `French theory' (Bourdieu, Derrida, Foucault et al.) has left its mark on the scholarly literature of information studies. A bibliometric analysis reveals which theorists (and which works) have been most highly cited over the course of the last four decades. The study also identifies the information studies journals and scholars who have been the most frequent citers of French theorists.
Spousal Support and Work—Family Balance in Launching a Family Business
Authors: Gudmunson Clinton G. , Danes Sharon M. , Werbel James D. , Loy Johnben Teik-Cheok
Published: April 2009

This study examines whether emotional spousal support contributes to business owners' perceived work—family balance while launching a family business. Hobfoll's Conservation of Resources theory of stress is applied to 109 family business owners and their spouses. Results from structural equation models support several hypotheses. First, reports of spousal support given are strongly related to reports of support received, suggesting genuine interpersonal transactions of support. Second, the effects of spousal support are confounded until a satisfaction-with-business-communication variable is introduced, revealing competing direct and indirect effects on work—family balance. Finally, business owner work hours have an additive negative effect on work—family balance, suggesting multiple means for maintaining work—family balance.
Toxic Interactions in the Rat Nose: Pollutants from Soiled Bedding and Methyl Bromide
Authors: Bolon Brad , Bonnefoi Marc S. , Roberts Kay C. , Marshall Marianne W. , Morgan Kevin T.
Published: April 2009

Interactions between test chemicals and pollutants can confound toxicology studies. To test the sensitivity of the regenerating olfactory epithelium to additional challenge with the olfactory epithelial toxicant methyl bromide (MeBr), Fischer 344 (F344) rats received 2 6-hr inhalation exposures (separated by a 28-day recovery period) to either 0 or 175 ppm MeBr. The regenerating epithelium was resistant to the second MeBr exposure. In addition, histopathologic examination revealed squamous epithelial hyperplasia in the vestibule; inflammation, epithelial necrosis, mucosal erosions, and squamous metaplasia of the respiratory epithelium in the anterior nose; and olfactory sensory cell loss in the dorsal medial meatus. These changes could not be attributed to MeBr, but they were correlated with housing in filter-capped cages between MeBr exposures and were presumably caused by volatile pollutants from soiled bedding. Moreover, olfactory sensory cell loss in the dorsal medial meatus was associated with local resistance to MeBr-induced damage in rats with pollutant-induced changes. Analysis of cage air revealed a progressive increase in ammonia levels between bedding changes (up to 50 ppm), but exposure to 300 ppm ammonia in an additional experiment reproduced only the anterior nasal lesions and not olfactory sensory cell loss. This study demonstrates that 1) regenerating olfactory epithelium is refractory to further MeBr toxicity; 2) pollutants from soiled bedding (in addition to ammonia) produce nasal lesions; and 3) pollutant-induced changes modify the nasal response to inhaled MeBr.
Hemorrhagic Cardiomyopathy and Hemothorax in Vitamin K Deficient Mice
Authors: Allen Anton M. , Hansen Carl T. , Moore Thomas D. , Knapka Joseph , Ediger Raymond D. , Long Philip H.
Published: April 2009

The cause of a fatal condition characterized by hemorrhagic cardiomyopathy, hemothorax, and coagulation defects in hysterectomy-derived male mice was investigated. Microscopic heart alterations included multifocal hemorrhage and necrosis with variable degrees of acute inflammation and fibroplasia that were most severe in the region of the atrioventricular junction. A spontaneous outbreak was arrested by increasing menadione Na-bisulfite (vitamin K) in the feed to 20 ppm. The complete syndrome including hemorrhagic cardiomyopathy was readily reproduced in germ-free male mice given a vitamin K-free diet, and in conventional male and female mice given Warfarin in the diet. We concluded that the cause of this condition was vitamin K deficiency.
Drug-Induced Hepatic Microgranulomatosis in Cynomolgus Monkeys
Authors: Mesfin Gebre M. , Higgins Michael J. , Thornburgh Bruce A. , Jones Brian W. , Vande Giessen Terri L. , Wickrema Sinha Asoka J.
Published: April 2009

This report discusses a unique drug-induced hepatotoxicity in cynomolgus monkeys treated orally with a novel potassium sparing experimental diuretic, [2,6-bis(4-chlorophenyl)-4-pyridinecarboxylic acid]. Groups of 6 adult male and female monkeys were treated orally with vehicle diluent, modified vehicle #122 or a suspension of the drug at 5.0, 12.5, or 32.0 mg/kg/day for 2 weeks. Another group of 5 monkeys were treated orally with 25.0 mg/kg/day of the drug for 2 weeks. Disposition of the drug was evaluated in 2 monkeys in the later group that received 27.4 mg/kg of radiolabelled drug on the 1st and last day of dosing. Hepatic toxicity was characterized biochemically, light and electron microscopically, histochemically, immunocytochemically, and toxico-kinetically. Conjugated serum bilirubin, alanine transaminase, and aspartate transaminase levels were increased in monkeys treated with over 12.5 mg/kg/day of the diuretic. The periacinar hepatic plates of monkeys treated with 25.0 or 32.0 mg/kg/day were distorted by accumulation of PAS and oil red-O positive multinucleated Kupffer cells. The cytosol of these cells was expanded by phagolysosomes containing granular materials of varying electron densities. Granular electron dense materials were also in endothelial cells and bile canaliculi. Fatty change, cholestasis, and rare piecemeal hepatic necrosis were minimal. The drug was primarily excreted through urine. Plasma concentration and half life of the drug were increased with multiple dosing. The highest concentration of unexcreted parent drug was in the liver. Drug-induced noninflammatory hepatic microgranulomatosis, apparently caused by sequestered drug-lipid/mucopolysaccharide complex in the phagocytic cells of the liver, can occur in any species, including humans, if orally administered xenobiotics are presented to the liver in particulate form.
Rat Urinary Bladder Hyperplasia Induced by Oral Administration of Carbonic Anhydrase Inhibitors
Authors: Molon-Noblot Sylvain , Boussiquet-Leroux Christine , Owen Roger A. , Irisarri Edmundo , Durand-Cavagna Genevieve , Peter Chennekatu P. , Duprat Pierre
Published: April 2009

The carbonic anhydrase inhibitors, acetazolamide and MK-0927, were given by oral route to male Sprague-Dawley rats at 200 mg/kg/day and 25 mg/kg/day, respectively, for up to 4 weeks. Sequential necropsies were performed and urinary bladders were examined by light microscopy (LM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Similar urinary bladder changes were seen with both compounds. SEM evidenced slight multifocal urothelial changes consisting of cell swelling, dissociation, degeneration, and exfoliation after 3 and 5 days of treatment. After 2 and 4 weeks of treatment, elevated or leafy microridges on the luminal cell surfaces were seen together with foci of swollen cells. After a 2-month-recovery-period, the urothelial surfaces were normal. LM and TEM showed multifocal vacuolation of the urothelium associated with inflammation of the underlying lamina propria after 3 and 5 days of treatment. Cellular hypertrophy and hyperplasia of the transitional epithelium was seen after a 5-day treatment, persisted without increasing severity after 2 and 4 weeks of treatment, and totally regressed after the recovery period. It was concluded that, in the rat urinary bladder, oral administration of acetazolamide and MK-0927 induced early degeneration and inflammation followed by epithelial regeneration, resulting in a reversible hyperplasia of the transitional epithelium.
Liver Tumors in Male Rats Following Treatment with Glucocorticosteroids
Authors: Ryrfeldt Ake , Squire Robert A. , Ekman Lars
Published: April 2009

Male rats treated with either budesonide, prednisolone, or triamcinolone acetonide in drinking water for up to 104 weeks developed slightly increased incidences of basophilic foci, and significantly increased incidences of combined hepatocellular adenomas/carcinomas as compared to controls. Based upon reduced body weight gains and survivals, the doses administered were considered to be toxic. It was concluded that the positive findings represented a class effect, and probably involved glucocorticoid receptors.
Intranuclear Inclusions in the Pituitary Gland of Cynomolgus Monkeys
Authors: Sinha Dinesh P. , Mitchell Maureen J.
Published: April 2009

In a 3-month oral toxicity study of a pharmaceutical agent, intranuclear inclusions were seen in the secretory cells of the pars anterior of the pituitary gland of 22 of 40 cynomolgus monkeys, with similar incidences in control and dosed groups. All monkeys were clinically healthy. Electron microscopic examination revealed that the intranuclear inclusions were cytoplasmic invaginations.
Hematological Effects of 2',3'-Dideoxycytidine in Rabbits
Authors: Riley Julia H. , Davidovich Alberto , Lipman Jack M. , Arceo Reynaldo , Anderson Timothy D.
Published: April 2009

The antiviral nucleoside analogue 2',3'-dideoxycytidine (ddC) is a DNA chain terminator and/or inhibitor of human immunodeficiency virus (HIV) reverse transcriptase. We evaluated the effects of ddC in 36 New Zealand white rabbits. Three/sex were assigned to a control group and 5 treatment groups (10-250 mg/kg/ day) for 13 or 18 weeks. Blood samples were taken 1 week prior to treatment and weekly thereafter to termination with the exception of the 2 highest dose groups, where blood sample collection was terminated at week 13. Selected hematological analytes were measured weekly with the exception of prothrombin time (PT) and activated partial thromboplastin time (APTT). PT and APTT and selected biochemical analytes were measured prior to treatment, at 7 weeks, and after 13 weeks of treatment. All rabbits were necropsied. Giemsa and hematoxylin and eosin sections were prepared from methacrylate-embedded marrow. Hematological effects included decreases in red blood cell count, hemoglobin, hematocrit, and white blood cell count and increases in mean corpuscular volume and red cell distribution width. Platelets, platelet volume, PT, APTT, and mean corpuscular hemoglobin concentration values were variable or unchanged. Effects were dose-related, most were seen at 1 week, and they persisted to term. Bone marrow histopathologic changes included megalocytosis, erythroid hypoplasia, bizarre erythroid nuclear morphology, nuclear-cytoplasmic asynchrony, and increased mitotic figures. Lymphopenia caused by ddC plateaued at 2 weeks and persisted until termination. Heteropenia (neutropenia) was sporadic. Biochemical values for serum analytes were unchanged by treatment. The principal hematological effect of ddC upon the erythron was characterized as a nonregenerative macrocytic anemia with erythroid hypoplasia and megaloblastic erythropoiesis. We consider the anemia to be of bone marrow origin because of the morphologic changes observed here and produced by the effect of ddC on DNA synthesis in erythroid precursors and/or stromal cells.
Morphology of Nasal Lesions Induced in Osborne-Mendel Rats and B6C3F1 Mice by Chronic Inhalation of Allyl Glycidyl Ether
Authors: Renne Roger A. , Brown H. Roger , Jokinen Micheal P.
Published: April 2009

Chronic (24-month) inhalation exposure to 5 or 10 ppm allyl glycidyl ether (AGE) induced nasal lesions in Osborne-Mendel rats and B6C3F1 mice. Inflammation, degeneration, regeneration, metaplasia, hyperplasia, and neoplasia were observed in the nasal mucosa. Squamous metaplasia and hyperplasia of the respiratory epithelium and degeneration and regeneration with subsequent squamous and/or respiratory metaplasia of the olfactory epithelium were observed in many AGE-exposed animals. Three primary nasal neoplasms (1 papillary adenoma, 1 squamous cell carcinoma, and 1 olfactory epithelial carcinoma) were observed in rats exposed to 10 ppm AGE, and 1 nasal papillary adenoma was observed in a rat exposed to 5 ppm. Four papillary adenomas and 2 hemangiomas were observed in the noses of mice exposed to 10 ppm AGE. Although the incidence of primary nasal tumors in AGE-exposed rats or mice was not statistically significant compared to the incidence in concurrent controls, the relative rarity of primary nasal tumors in historical controls and the concurrent presence of metaplastic and hyperplastic nasal lesions similar to those reported to be associated with induced tumors of nasal epithelia by other chemicals suggest that the nasal tumors observed may be related to AGE exposure. It was concluded that, in addition to lesions indicating a toxic effect on the nasal mucosa, inhalation exposure to AGE for 24 months resulted in some evidence of carcinogenicity of AGE for male mice, equivocal evidence of carcinogenicity for female mice and male rats, and no evidence of carcinogenicity for female rats.
Leukocyte Response to Toxic Injury
Authors: Weiss Douglas J.
Published: April 2009

Exposure to a variety of drugs and toxins can induce hematopoietic damage. These agents exert their effects through several distinct mechanisms including destruction or suppression of hematopoietic stem cells, cytotoxic destruction of rapidly proliferating precursor cells, immune-mediated hematotoxicity, altered hematopoietic microenvironment, genetic mutation, and microvascular injury. Some toxins consistently produce suppression of granulopoiesis in a dose-dependent manner, whereas others produce idiosyncratic reactions. Although all types of injury tend to result in granulocytopenia, the time course of the changes varies with the type of injury. With acute destruction of the proliferative pool of granulocytes, neutropenia develops within 7 days and recovery occurs within days after discontinuing treatment. With stem cell injury, the onset of hematotoxicity is variable and damage is often permanent. Immune-mediated reactions may occur acutely or after months or years of treatment with a drug. Drugs or toxins that act as mutagens can induce a variety of hematopoietic disorders including aplastic anemia, myelodysplasia, and leukemia. Therefore, the time course of onset of leukopenia after drug or chemical exposure and the rapidity of hematopoietic recovery give clues to the mechanism by which granulopoiesis is suppressed.
Assessment of Hemolytic and Hemorrhagic Anemias in Preclinical Safety Assessment Studies
Authors: Mcgrath John P.
Published: April 2009

The general characteristics of anemia and the distinguishing features of hemolytic, hemorrhagic, hypo-proliferative, maturation abnormality, and iron-deficiency anemias are described. Hemolytic anemias are differentiated initially from hemorrhagic anemias by excluding hemorrhage on clinical, necropsy, or histologic examination. Next, they are distinguished from the remaining types of anemia on the basis of higher reticulocyte counts or, in some instances, by the very rapid rate of decline of the PCV. Hemolytic anemias are distinguished from each other on the basis of incidence and the presence or absence of a dose-response (idiosyncratic vs toxic) and by the cause of hemolysis (oxidative, nonoxidative, or immune-mediated). Hemorrhagic anemias are subclassified on the basis of single- and multiple-site hemorrhage. The causes of multiple-site hemorrhage (hemostasis dysfunction) are established by first- and second-line tests, the type of bleeding, clinical data, and the information gained from an evaluation of the structure, activity, and metabolism of the compound.
Nasal Diagrams: A Tool for Recording the Distribution of Nasal Lesions in Rats and Mice
Authors: Mery Stéphane , Gross Elizabeth A. , Joyner Donald R. , Godo Matthew , Morgan Kevin T.
Published: April 2009

Knowledge of patterns of lesion distribution can provide insight into the relative roles played by regional tissue dose and local tissue susceptibility in toxic responses to xenobiotics in the nose and assist assessment of potential human risk. A consistent approach is needed for recording lesion distribution patterns in the complex nasal airways of rats and mice. The present work provides a series of diagrams of the nasal passages of the Fischer-344 rat and B6C3F1 mouse, designed for mapping nasal lesions. The diagrams present each of the major cross-sectional airway profiles, provide adequate space for nasal mucosal lesion recording, and are suitable for duplication in a commercial photocopier. Sagittal diagrams are also provided to permit transfer oflesion location data observed in transverse sections onto the long axis of the nose. The distribution of lesions induced by a selected range of xenobiotics is presented. Approaches to application of the diagrams and interpretation of results obtained are discussed in relation to factors responsible for lesion distribution in the nose and their relevance to interspecies extrapolation. A modified approach to anatomical classification of the ethmoturbinates of the rodent is also presented.
Dissimilar Frequency of Hepatoblastomas and Hepatic Cystadenomas and Adenocarcinomas Arising in Hepatocellular Neoplasms of D2B6F1 Mice Initiated with N-Nitrosodiethylamine and Subsequently Given Aroclor-1254, Dichlorodiphenyltrichloroethane, or Phenobarbital
Authors: Diwan Bhalchandra A. , Ward Jerrold M. , Kurata Yasushi , Rice Jerry M.
Published: April 2009

Aroclor-1254 (Ar-1254) and dichlorodiphenyltrichloroethane (DDT) were compared to phenobarbital (PB) for their ability to promote hepatocellular proliferative lesions to hepatocellular adenomas and carcinomas and to hepatoblastomas in D2B6F1 male mice initiated with N-nitrosodiethylamine (NDEA). Hepatocellular neoplasms developed in all mice given NDEA and were more numerous in mice fed promoters. Multiplicities decreased in the order Ar-1254 > PB > DDT, indicating that Ar-1254 was more potent than either PB or DDT at the dosage levels used. PB was the most effective of the 3 agents in stimulating the evolution of hepatocellular neoplasms to hepatoblastoma. The incidence of hepatoblastomas in the NDEA.PB group was 72% but was only 27% in NDEA-initiated, DDT-promoted mice and 33% in low-dose and only 9% in high-dose Ar-1254-promoted mice. In contrast, lesions resembling benign and malignant cholangiocellular neoplasms were frequently found within hepatocellular tumors in Ar-1254-promoted mice but not in mice fed PB or DDT, either alone or after NDEA. Some cystic glandular structures in Ar-1254-promoted mice contained mucous cells, argentaffin cells, and Paneth cells and thus constituted intestinal metaplasia. Hepatoblastoma and intestinal metaplasia/cholangiocellular tumor morphology appear to constitute different patterns of genetic programming induced by certain promoters in expanding clones of initiated hepatocytes, on favorable genetic backgrounds such as that of D2B6F1 male mice.
Constipation and Megacolon in Rats Related to Treatment with Oxodipine, a Calcium Antagonist
Authors: Nyska Abraham , Waner Trevor , Galiano Alvaro , Fich Abraham
Published: April 2009

The constipatory effects of oxodipine, a dihyrdopyridine-type calcium antagonist, have been described in a 3-mo, 12-mo, and 30-mo feeding toxicity study in rats. This paper reports the occurrence of megacolon in rats as a result of the constipatory effects of chronic administration of oxodipine. The first mortality due to oxodipine was seen after about 1 yr of treatment at a dose of 225 mg/kg/day. The toxic effects noted were dose-, time-, and sex-related. Female rats appeared more sensitive to the constipatory effects of the drug. The dose at which the effect occurred in both male and female rats was from about 75 to 675 times the recommended therapeutic dose for humans. To the best knowledge of the authors, this is the first report of a calcium channel blocker causing constipation in rats.
Histopathological and Ultrastructural Changes in the Juxtaglomerular Apparatus of the Rat Following Administration of ZENECA ZD6888 (2-ethyl-5,6,7,8-tetrahydro-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)-methoxylquinoline), an Angiotensin II Antagonist
Authors: Jackson David G. , Jones Huw B.
Published: April 2009

Male and female Alderley Park rats were treated for 26 wk with ZENECA ZD6888, an angiotensin II (All) antagonist, at doses of 25, 50, and 250 mg/kg/day and the kidneys examined by light and electron microscopy. Nephropathy (tubular degeneration and regeneration), thickening of the basal lamina, mononuclear cell infiltration, and hypertrophy and hyperplasia of the juxtaglomerular apparatus were seen by light microscopy. Ultrastructurally, juxtaglomerular cell granules were increased in number and displayed substantial structural heterogeneity. In some cells, granules contained paracrystalline inclusions while others consisted predominantly of myelinic debris. Evidence ofconversion of arteriolar smooth muscle cells into juxtaglomerular cells and their degeneration was also obtained by electron microscopy. The juxtaglomerular changes were treatment- and dose-related and were attributed to an exaggerated pharmacological action of the compound, that is, ZD6888-mediated blockade of All receptors leading to competitive inhibition of the All-mediated release of renin. The resemblance between the findings seen in the present study following administration of an All antagonist and those due to angiotensin-converting enzyme inhibitors reported by others was striking.
Changes Associated with Long-Term Oral Administration of the Penem Antibiotic FCE 22891 to Rats and Monkeys with Particular Emphasis on the Urinary Tract and the Urine
Authors: Brughera Marco , Iatropoulos Michael J. , Scampini Giovanna , Moneta Donatella , Mazué Guy , Newman Arthur J.
Published: April 2009

FCE 22891, a synthetic β-lactam antibiotic of the penem class, was administered by gavage to Sprague-Dawley rats and cynomolgus monkeys for 26 wk (with and without a 6-wk recovery). Rats received the test material at doses of 0, 200, 500, and 1,250 mg/kg/day, and monkeys were given doses of 0, 100, 200, 400, and 600 mg/kg/day. At the end of the 26-wk treatment period, approximately two-thirds of the animals (both species) were sacrificed, and the remaining animals were held without treatment for a further 6 wk. A treatment-related mortality occurred in female monkeys receiving 600 mg/kg. There was a reduction in body weight gain in the high-dose groups of both species. Male rats were more affected than the females and, conversely, female monkeys were affected more than the males. At higher dose levels, both species exhibited an early, but transient, azotemia and oliguria with an increase in specific gravity and reduced pH. In rats, microscopic examination revealed treatment-related renal cortical tubular degenerative and regenerative changes with associated interstitial inflammation and fibrosis and diffuse urothelial hyperplasia in the urinary bladder. In general, female rats were less severely affected, and in both sexes there was a trend to recovery of most of these effects. In monkeys given 600 mg/kg of the test material, renal cortical tubular degeneration was seen only in those females that died in the first 5 wk of dosing. In other animals at this dose level, the renal lesions were determined to be reversible.
Establishment of an Animal Model for Pulmonary Fibrosis in Mice Using Monocrotaline
Authors: Hayashi Shuji , Mitsumori Kunitoshi , Imaida Katsumi , Imazawa Takayoshi , Yasuhara Kazuo , Uneyama Chikako , Hayashi Yuzo
Published: April 2009

A preliminary attempt at experimental induction of pulmonary fibrosis in which male ICR mice received 15 weekly sc injections of 200 or 100 mg/kg monocrotaline (MC) revealed that most animals treated with the larger dose died of severe interstitial pneumonia, whereas those given 100 mg/kg exhibited only relatively slight lung injury. Based on these results, male mice were administered sc injections of 200 and 100 mg/kg MC once a week for 9 and 18 times, respectively, and then maintained without any further treatment until week 28 after the start. Mice treated with 200 mg/kg MC showed severe pulmonary damage and died by week 25. Mortalities also occurred in the 100-mg group from week 16, with 11 of 40 animals surviving at the termination of the experiment. Histologically, both dose groups demonstrated severe interstitial pneumonia and/or pulmonary fibrosis. Ultrastructurally, inflammatory edema possibly attributable to injuries of alveolar capillary endothelial cells was observed in the high-dose group at week 8, and there was a remarkable increase in collagen fibers in alveolar septa in this group thereafter. The present study results suggest that lung injuries induced by MC treatment progress to irreversible lung fibrosis and that this animal model may have advantage for studying the pathogenesis of lung cancers in patients with pulmonary fibrosis.
The Use of In Vitro Metabolism Techniques in the Planning and Interpretation of Drug Safety Studies
Authors: Wrighton Steven A. , Ring Barbara J. , Vandenbranden Mark
Published: April 2009

An important issue in toxicology is the suitability of the data obtained with experimental animals for human risk assessment. Because it is not possible to use humans in long-term toxicological studies, the use of animals will continue. However, the data obtained in animal studies can be better extrapolated to the patient by utilizing bridging studies with in vitro models of human drug metabolism. There are 2 basic categories of in vitro methods for the examination of human liver drug metabolism. The first group of in vitro methods consists of the cellular models, which include primary hepatocytes, liver slices, and cell lines. The second group is the use of preparations of the drug-metabolizing enzymes such as tissue homogenates, subcellular fractions, and isolated enzymes. Studies modeling both the human and experimental animal metabolism of a drug are useful in the design of toxicological studies. In vitro studies can identify metabolites, species-specific metabolic routes, and the experimental animal model that best reflects the potential human exposure to the drug and its metabolites. This information can also be useful in the design of the clinical studies by identifying human metabolites, the enzymes responsible for the metabolic clearance of the drug, the effects of genetics and other host factors on the metabolism of the drug, and potential drug-drug interactions. An example of how such information is generated and interpreted is presented.
Peripheral Neuropathy Induced by Intravenous Administration of Vincristine Sulfate in the Rabbit.
Authors: Fiori Mario G. , Schiavinato Antonella , Lini Elisabetta , Nunzi Maria Grazia
Published: April 2009

The lack of a suitable animal model for the peripheral neuropathy that often follows the systemic administration of the chemotherapeutic agent vincristine sulfate (VCR) has hampered the correlation between experimental and clinical patterns of this neuropathy. New Zealand rabbits have been recently found to develop, after iv injection of a VCR total dosage similar to that used in humans, a peripheral polyneuropathy characterized by electrophysiological changes that overlap those observed in the clinical setting. The present study was aimed at investigating the ultrastructural features of 3 different nerves (sural, peroneal, and medial gastrocnemius) in rabbits treated with 3 VCR doses that fall within the range (0.2-0.3 mg/kg iv) known to be efficacious chemotherapeutically and active neurotoxicologically. Regardless of the dose and the nerve under examination, histopathologic alterations appeared in the form of an overall loss of myelinated fibers, accompanied by successful attempts of regeneration and remyelination. Fibers undergoing Wallerian degeneration were characterized by an axoplasm, which was either watery-flocculent or divided in 2 or more regions as a consequence of ingrowing Schwann cell processes from the adaxonal surface. These ingrowths tended to isolate axoplasmic areas, retaining a fairly normal structure from other areas already crowded with altered organelles and cytoskeletal elements. In any event, neurofibrillary accumulations were rarely seen. These patterns are discussed with reference to those reported in the ultrastructural studies of human cases and confirm the suitability of rabbit as an animal model for VCR-induced peripheral neuropathy.
Alterations in Microtubules, Intermediate Filaments, and Microfilaments Induced by Microcystin-LR in Cultured Cells
Authors: Wickstrom Mark L. , Khan Safdar A. , Haschek Wanda M. , Wyman John F. , Eriksson John E. , Schaeffer David J. , Beasley Val R.
Published: April 2009

Microcystin-LR (MCLR) is a cyanobacterial hepatotoxin that inhibits intracellular serine/threonine protein phosphatases causing disruption of actin microfilaments (MFs) and intermediate filaments (IFs) in hepatocytes. This study compared the effects of MCLR on the organization of MFs, IFs, and microtubules (MTs) in hepatocytes and nonhepatocyte cell lines and determined the sequence of toxin-induced changes in these cytoskeletal components. Rat renal epithelial cells and fibroblasts were incubated with MCLR at 100 or 200 μM for 6-18 hr. Rat hepatocytes in primary culture were exposed to the toxin at 1 or 10 μm for 2-64 min. Cells were fixed and incubated with primary antibodies against β-tubulin, actin, and vimentin or cytokeratin IFs, followed by gold-labeled secondary antibodies with silver enhancement of the gold probe. The fraction of fibroblasts and hepatocytes with altered cytoskeletal morphology was evaluated as a function of MCLR dose and exposure time to assess the sequence of changes in cytoskeletal components. Changes in fibroblasts and some hepatocytes were characterized initially by disorganization of IFs, followed rapidly by disorganization of MTs, with the progressive collapse of both cytoskeletal components around cell nuclei. Many hepatocytes exhibited MT changes prior to effects on IF structure. Alterations in MFs occurred later and included initial aggregation of actin under the plasma membrane, followed by condensation into rosette-like structures and eventual complete collapse into a dense perinuclear bundle. The similarity of effects among different cell types suggests a common mechanism of action, but the independent kinetics of IF and MT disruption in hepatocytes suggests that there may be at least 2 sites of phosphorylation that lead to cytoskeletal alterations.
Oropharyngeal Granulomas and Tracheal Cartilage Degeneration in Fischer-344 Rats
Authors: Germann Paul-Georg , Ockert Deborah , Tuch Klaus
Published: April 2009

The development of tracheal cartilage degeneration and inflammation of the seromucinous glands of the oropharynx may be a factor causing early mortalities in long-term studies with Fischer-344 (F-344) rats. The presence of these lesions was investigated in groups of male and female F-344 rats killed at 6, 19, and 32 wk of age. Half of the rats killed at 19 and 32 wk of age were sham treated with water (pH 10) by daily oral gavage for a duration of 13 or 26 wk prior to autopsy in order to detect any influence on the laryngotracheal cavity due to dosing technique. A clear age-associated increase in severity and incidence of chondroid degeneration of the tracheal and laryngeal cartilage was revealed, with an onset as early as 6 wk of age. After 19 wk, a high frequency of oropharyngeal granuloma formation was found. No relationship of the lesions to the gavage technique was apparent. The F-344 rat strain may possess a predisposition for inflammatory and degenerative changes in the oropharyngeal and laryngotracheal cavity, changes that can lead to increased and unexpected mortality rates in nonclinical safety studies (7).
The Morphology of Juxtaglomerular Cell Hyperplasia and Hypertrophy in Normotensive Rats and Monkeys Given an Angiotensin II Receptor Antagonist
Authors: Owen Roger A. , Molon-Noblot Sylvain , Hubert Marie-Françoise , Kindt M. Victoria , Keenan Kevin P. , Eydelloth Ronald S.
Published: April 2009

L-694,492 (DUP 532), an angiotensin II (AII) receptor antagonist, was given orally at 125 mg/kg/day to rats and monkeys for up to 6 mo to assess the effects of the compound on juxtaglomerular (JG) cells. In rats, mild JG cell hypertrophy/hyperplasia occurred and was associated with a 12-fold increase in the bromodeoxyuridine-labeling index of JG cells and a 10-fold increase in renal renin content. Ultrastructurally, intermediate cells with characteristics of both smooth muscle cells and granulated renin-producing cells as well as hypertrophied renin-synthesizing cells were seen in the afferent arterioles. In monkeys, marked hypertrophy and hyperplasia were seen with an 80% increase in JG cell numbers, mitotic activity, and a greatly increased renin content compared to controls. Three mo after drug withdrawal, an increased number of cells remained, which showed features of smooth muscle cells with essentially no renin. These results show that AII receptor antagonism stimulates increased renal renin production by hypertrophy of existing granulated cells, metaplasia of smooth muscle cells to renin-synthesizing cells, and cell proliferation. When treatment was discontinued, the renin-producing cells redeveloped the features of smooth muscle cells, but, as we have shown with enalapril (angiotensin-converting enzyme inhibitor), the increase in their number persists for at least 3 mo.
Histologic Study of the Femoral Growth Plate in Beagle Dogs
Authors: Yamasaki Kanji
Published: April 2009

The femora of normal-growing beagle dogs were examined histologically at 6 and 12 mo of age to clarify the morphologic changes occurring in the femoral growth plate as background data for studies of chondroosseous toxicology. Enchondral ossification was active at 6 mo of age, and the growth plate disappeared at 12 mo. The growth plate showed degradation of the matrix and destructive lesions at 6 mo of age. Degradation of the matrix was observed between the chondrocytic columns accompanied by degeneration and disappearance of chondrocytes. Destructive changes were seen in the epiphyseal hyaline cartilage and proliferating and hypertrophic zones, resulting in disarrangement of the chondrocytic columns. Furthermore, abnormal chondrocytic proliferation of the epiphyseal hyaline cartilage zone and cleftlike fractures between the growth plate and cortex were frequently present. No abnormalities were detected in the articular cartilage at 6 and 12 mo of age.
Characterization of the Pulmonary Lesions Induced in Rats by Human Recombinant Interleukin-2
Authors: Jun Zhang  , Wenthold Robert J. , Yu Zu-Xi , Herman Eugene H. , Ferrans Victor J.
Published: April 2009

Histologic, electron microscopic, and immunohistochemical studies were made to analyze the structural features and the cellular composition of the pulmonary lesions produced in rats by the administration of interleukin-2 (IL-2). This agent induced pulmonary edema; thickening of alveolar septa; damage to endothelial cells in capillaries and venules, marked interstitial infiltration by cytotoxic T lymphocytes, lymphokine-activated killer (LAK) cells, macrophages, and dendritic cells (as demonstrated by cell counting in preparations stained immunohistochemically with peroxidase- and fluorochrome-labeled antibodies); and injury to bronchiolar and alveolar epithelial cells. Granular and agranular lymphocytes often were closely apposed to endothelial cells in capillaries and venules. Contacts between lymphocytes and type II alveolar epithelial cells also were observed. Damaged type II alveolar epithelial cells showed nuclear and cytoplasmic features that are considered indicative of apoptosis (confirmed by nick end labeling). Phagocytosis of apoptotic bodies by macrophages was occasionally found. These results support the concept that IL-2 induces cytotoxic vascular and parenchymal cell damage that is mediated by LAK cells and cytotoxic T lymphocytes, which make contacts with endothelial cells and type II alveolar epithelial cells. This damage appears to be exacerbated by the secondary release of a variety of vasoactive agents and inflammatory mediators.
Spontaneously Occurring Mammary Adenocarcinoma in a 10-wk-old Female Rat
Authors: Oishi Yuji , Yoshizawa Katsuhiko , Suzuki Junya , Makino Natsuyo , Hase Kikumi , Yamauchi Kenji , Tsubura Airo
Published: April 2009

A spontaneous mammary adenocarcinoma was detected in a 10-wk-old female virgin Sprague-Dawley rat in a subacute toxicity study for safety assessment. The rat was sacrificed according to the study schedule at 23 wk of age and was subjected to complete necropsy. Gross pathological examination revealed that the tumor had reached 20 x 35 x 45 mm. It was settled in the right posterior abdominal subcutaneous tissue and had not invaded the surrounding tissues. Histopathologically, it was diagnosed as a typical mammary adenocarcinoma of rats. In our literature search, we found no previous reports of spontaneous adenocarcinomas of the mammary gland in such a young rat. Therefore, attention should be paid to the fact that mammary adenocarcinomas can occur spontaneously at an early age in rats.
Polymerase Chain Reaction and In Situ Hybridization: Applications in Toxicological Pathology
Authors: Malarkey David E. , Maronpot Robert R.
Published: April 2009

Polymerase chain reaction (PCR) and in situ hybridization (ISH) have revolutionized the study of genes and gene expression, and many of these molecular biology advances will greatly impact research in toxicological pathology. PCR is one of the most powerful tools in molecular biology and involves primer-mediated enzymatic in vitro amplification of specific target DNA sequences. Recent innovative methods utilizing PCR technology have been developed to detect mutations in neoplastic and small subpopulations of cells, to study biomarkers of genetic susceptibility and genes involved with carcinogen metabolism, to estimate mutation frequencies, to find novel genes induced by chemical exposure, and to characterize gene expression. ISH provides data on individual cells rather than an average of total cellular populations and allows analysis for heterogeneity. When combined with PCR. the sensitivity of ISH is elevated, and single-copy DNA sequences, single-base mutations, or low copies of messenger RNA (mRNA) can potentially be detected within individual cells. Herein are reviewed ISH- and PCR-based techniques such as single-strand conformation polymorphism analysis to detect point mutations, allelotypic analysis for loss of heterozygosity, differential display of mRNA to characterize gene expression, quantitative reverse transcriptase polymerase chain reaction, and in situ polymerase chain reaction with emphasis on current or potential applications in toxicological pathology. These new and evolving techniques offer tremendous potential in providing new insights into the molecular basis of toxicity and carcinogenesis.