bluuebunny/crossref_metadata_2025 huggingface dataset:
Music, media and urban mythscapes: a study of the ‘Canterbury Sound’
Authors: Bennett Andy
Published: April 2009

The purpose of this article is twofold. First, to illustrate how recently developed technologies are giving rise to new ways of conceptualizing the relationship between music and place. Applying the concept of mythscapes, developed from Appadurai’s work, to the ‘Canterbury Sound’, a term recently revived and adapted by a website-centred fanbase to describe a loosely defined back-catalogue of albums, songs and home-recorded musical experiments, the article argues that the city of Canterbury is being inscribed with a series of urban myths relating to its perceived role in the creation of a musical style deemed by fans to be locally specific. Second, through its analysis of the Canterbury Sound’s ‘construction’ on the Internet, the article considers the extent to which the Canterbury Sound can be considered a ‘virtual’ scene, Internet communication replacing more conventional forms of celebrating collective musical taste as these emerge through the sociality of club, concert hall and festival-based scenes.
The ecology of online newspapers: the case of China
Authors: He Zhou , Zhu Jian-hua
Published: April 2009

This article examines the development of online newspapers in China through a ‘social environment’ framework and finds several adverse factors in policies, regulations, economic structure, business conventions and telecommunications infrastructure. Through a ‘virtual community’ framework, it analyzes the operation and content of those newspapers and finds that they are still in a primitive stage of ‘virtual communities’. The article’s contribution to the field lies not only in its exploration of what is behind the development of online newspapers in China, but also in that it has developed two conceptual frameworks that are of universal interest in the study of online publications.
Vagueness, familiarity and social realism: making meaning of radio soap opera in south-east Afghanistan
Authors: Skuse Andrew
Published: April 2009

This article explores some of the semantic linkages that exist between the producers and consumers of a BBC World Service radio soap opera, produced for Afghanistan. Few ethnographic studies of mass media have tackled both production and consumption; the dominant preference within this emerging sub-discipline favours audience studies and makes unsubstantiated inferences concerning production regimes. This article takes analysis a crucial step forward to examine how the dramatic context of radio soap opera is defined and represented by producers, and appropriated and manipulated by listeners. Via discussion of the opposed categories of vagueness and familiarity, the social realist pretensions of the production - addressed through the criteria of place, voice, sound and language - are assessed against a range of audience readings of this representation of reality. The article concludes by stating that whilst social realism is aspired to and actively pursued by the soap opera’s writers and producers, it is only invested with meanings that are specific and socially located, upon contact with the audience.
The MIT Media Lab: techno dream factory or alienation as a way of life?
Authors: Hassan Robert
Published: April 2009

This article critically analyses the work and the ethos of the MIT Media Lab in the context of globalizing capital and the ICT revolution. It argues that the Media Lab owes its tremendous success in part to the public relations strategies of its founder, Nicholas Negroponte, and to the very real need for the Lab’s products to ‘fill in the gaps’ left by the broad and irregular dynamics of globalization and the ICT revolution. The Media Lab and its research products insert information technologies into the interstices of cultural, social and temporal life, stitching together an ‘informational ecology’ of interconnectivity. This ecology has its own temporality, a synchronized ‘chronoscopic’ temporality or real-time duration that obliterates the many other temporalities that interpenetrate our lives and give them meaning. It is argued the ‘informational ecology’ of interconnectivity constructed by the Media Lab and many other emulative ‘start-ups’, lead not to a world of ‘diversity’ as Negropontean philosophy insists, but a one-dimensional world of alienation.
Articulating complex information needs using query templates
Authors: Vechtomova Olga , Hao Zhang
Published: April 2009

In this paper we investigate the effectiveness of topic-independent query templates as a tool for assisting users in articulating their information needs. We hypothesize that topic-independent query templates can help users with complex information needs to express their requirements more accurately and in greater detail. We developed a set of query templates representing general semantic relationships between concepts, such as cause—effect and problem—solution. Each template was written in the form of a fill-in-the-blanks question. A user study was performed comparing the template-based interface with a single-textbox search interface. Results demonstrate that, while users found the template-based query formulation less easy to use, the queries written using templates performed better than the queries written using the control interface with one query textbox.
Testicular Damage Caused by Inhalation of Ethylene Oxide in Rats: Light and Electron Microscopic Studies
Authors: Kaido Masanobu , Mori Koji , Koide Osamu
Published: April 2009

Although testicular damage caused by ethylene oxide vapor (EtO) has been previously reported, the morphological changes occurring in seminiferous tubules remain unclear. We examined the time course of the testicular lesion induced by EtO in order to clarify its morphogenesis. Wistar rats were exposed to 500 ppm EtO for 6 hr per day, 3 times per week for 2, 4, 6, or 13 weeks through inhalation. In the 2-week exposure group, Sertoli cells often showed condensation and retraction of the cytoplasm, and dilatation of the endoplasmic reticulum (ER). In apical Sertoli cells, processes which encapsulated the heads of elongate spermatids, ectoplasmic specializations, and tubulobulbar complexes were often deformed and many elongate spermatids were degenerated. In the 4- and 6-week exposure groups, many degenerated Sertoli cells were present, and deformed germ cells, sometimes with multinucleation, appeared to make direct contact with each other without interlocation of Sertoli cell lateral processes. A few scattered immature Sertoli cells were evident in the 6-week exposure group. In the 13-week exposure group, seminiferous tubules containing almost all types of germ cells reappeared, mixed with atrophic tubules containing Sertoli cells only. In the former tubules, Sertoli cells often possessed regularly regenerated lateral processes, which were interposed between germ cells. These results indicate that the germ cell damage may be associated with damage to Sertoli cells. In spite of the intermittent exposure, focal regeneration of Sertoli cells appeared after 6 weeks of exposure to EtO and preceded patchy recovery of germ cells. Therefore, the data suggest that Sertoli cell regeneration may permit regeneration of germ cells.
Histologic Methods and Interspecies Variations in the Laryngeal Histology of F344/N Rats and B6C3F1 Mice
Authors: Renne Roger A. , Gideon Katherine M. , Miller Rodney A. , Mellick Paul W. , Grumbein Sondra L.
Published: April 2009

The relatively high incidence and variety of lesions induced in the upper respiratory tract of rodents by inhalation of xenobiotics has resulted in considerable attention given to the microscopic anatomy of this area. Specific areas of the rodent laryngeal mucosa appear to be more sensitive to inhaled materials and more likely to contain cellular changes in response to injury. These include the epithelium covering the base of the epiglottis, ventral pouch, and the medial surfaces of the vocal processes of the arytenoid cartilages. There are few good landmarks for trimming rodent larynges to get consistent and accurate sections through these target areas. We have obtained consistently reproducible results by cutting transversely through the easily palpable cricothyroid notch and embedding the entire larynx anterior to this in paraffin with the cut surface against the face of the block. Multiple sections are cut from the caudal larynx toward the epiglottis, unstained sections examined microscopically for orientation, and sections from target areas selected for staining and histopathologic examination. Routine use of these methods for preparation and microscopic examination of sections of the larynx has revealed some variations in normal laryngeal anatomy between Fischer 344 (F344/N) rats and B6C3F1 mice.
Hepatic Morphologic and Biochemical Changes Induced by Subacute Cocaine Administration in Mice
Authors: Powers James F. , Alroy Joseph , Shuster Louis
Published: April 2009

The initial event and site of cocaine-induced hepatic injury have not been elucidated. In an attempt to identify the minimal effective dose and the site of injury, we have examined the livers of mice exposed to small daily doses of cocaine, using morphological and biochemical methods. All doses of cocaine greater than 5 mg/kg were able to cause significant elevation of serum glutamic pyruvic transaminase. Light microscopy revealed a progression of centrilobular necrosis as the dose increased from 10-30 mg/kg. The initial morphologic changes observed prior to necrosis included aggregation of intermediate filaments and dilation of rough endoplasmic reticulum with loss of ribosomes. Immunohistochemistry, using antibodies to cytokeratins, showed staining of individual hepatocytes in livers from cocaine-treated animals but not in controls. In contrast to earlier reports, we found little, if any, disruption of mitochondria. In vitro, the direct application of cocaine, norcocaine, and N-hydroxynorcocaine on isolated mitochondria had no effect on the ADP:O or respiratory control ratios, at concentrations up to 2.0 mM. Our studies demonstrate that any early cellular alterations in cocaine-induced hepatic injury are manifested in intermediate filaments and endoplasmic reticulum with no evidence of mitochondrial involvement.
Histopathological Effects in Poecilia reticulata (Guppy) Exposed to Methyl Mercury Chloride
Authors: Wester Piet W. , Canton Hans H.
Published: April 2009

To evaluate the usefulness of histopathology in aquatic toxicity testing, studies were carried out on the small freshwater fish Poecilia reticulata (guppy) following aqueous methyl mercury chloride exposure. Fish were exposed to concentrations of 0, 1.0, 1.8, 3.2, 5.6, or 10 μg/L for 1 and 3 months. Histopathological changes included the occurrence of multiple granulomas in various tissues, in particular, the integument and orbit. These changes were accompanied by hyperplasia of monocytopoietic interrenal tissue, and hepatocellular change which was confirmed by morphometry. The latter findings were probably a result of monocyte "consumption" by granulomas, and hepatic synthesis of ("stress") proteins, respectively. The bile duct and, focally, the proximal intestine, showed hyperplasia of the epithelium. In the testis of sexually mature fish (3-month study), degeneration and necrosis of sperm occurred, with severe cases exhibiting Sertoli cell hypertrophy, interstitial inflammation, and absence of mature sperm. Epidermal mucous cells disappeared in the highest concentration used, and, after 3 months, clusters of undifferentiated basophilic cells were seen in the gas gland, which occasionally were suggestive of malignant growth. The changes in the kidney tubules were characterized by degeneration and necrosis of single cells which also showed mitotic figures. This is considered a result of the mitosis-disturbing activity of methyl mercury (MeHg). It is concluded that MeHg has effects on various target organs in guppies with the occurrence of granulomas as the most sensitive indicator, yielding a no-observed-effect concentration (NOEC) of 1.0 μg/L. In contrast to mammalian species, no morphologic evidence for neurotoxicity was found.
Spontaneous Renal Neoplasms in Aged Crl:CD®BR Rats
Authors: Zwicker Gary M. , Eyster Randy C. , Sells Donald M. , Gass Jerome H.
Published: April 2009

Primary neoplasms of the kidneys occurred in 11/682 male (1.6%) and 2/694 female (0.3%) Crl:CD®Br strain Sprague-Dawley rats. Eight of 13 neoplasms were of mesenchymal origin and 5 of 13 were epithelial. Five neoplasms were lipoma (3) or liposarcoma (2). Three of 13 were either hemangioma (1) or mesenchymal tumors (2). The epithelial neoplasms were carcinomas. There was no microscopic evidence of metastasis among those neoplasms judged malignant on morphologic criteria. The overall natural incidence in males was nearly double that compiled for this strain while in females the incidence was similar to that reported for other females.
Experimental Renal Papillary Necrosis in the Mongolian Gerbil (Merianes unguiculatus)
Authors: Wolf Douglas C. , Carlton William W. , Turek John J.
Published: April 2009

Sequential light microscopic and ultrastructural examination of kidneys from male and light microscopic examination of female Mongolian gerbils given 250 mg 2-bromoethylamine hydrobromide (BEA)/kg body weight ip were performed. In addition, male Mongolian gerbils were treated with both BEA and ip injections of either water, dimethyl sulfoxide, piperonyl butoxide, or reserpine. Light microscopic renal lesions in male Mongolian gerbils progressed from congestion of the vasa recta of the proximal inner medulla at 6 hr post-treatment to total renal papillary necrosis (RPN) at 24 hr post-treatment. There was no sex difference in sensitivity to BEA. Ultrastructural alterations in male gerbils were restricted to the vasa recta. Vascular lesions of endothelial swelling and pericapillary edema in the vasa recta of the proximal inner medulla was observed 2 hr post-treatment and progressed to occlusion by platelets adherent to exposed basement membranes at 6 hr post-treatment. Diuresis induced by injections of saline and injections of dimethyl sulfoxide or piperonyl butoxide did not affect the development of BEA-induced RPN. Reserpine slowed the development of BEA-induced RPN by its vasodilatory effect on the renal vasculature, not by blocking the endothelial toxicity of BEA. RPN induced by BEA in the Mongolian gerbil is apparently an ischemic necrosis of the inner medulla that develops secondary to endothelial damage of the vasa recta.
Parenteral Aluminum Compounds Produce a Local Toxic Myopathy in Rats: Importance of the Anion
Authors: Levine Seymour , Saltzman Arthur , Drakontides Anna B.
Published: April 2009

Aluminum lactate, injected in rats, produced skeletal muscle necrosis of diaphragm and abdominal wall subjacent to peritoneal surfaces. Deeper muscle cells (distal from inoculum) were less severely affected. Ultrastructural studies of diaphragm revealed inoculum coating collagen fibrils, aggregating next to muscle basal lamina and localized within phagocytes. Aluminum lactate penetrated lymphatic vessels and caused reactive changes on the pleural as well as peritoneal surfaces of diaphragm. In contrast, injection of aluminum citrate did not produce myopathy. Also, mixtures of aluminum lactate with aluminum citrate, sodium citrate, or another chelating agent failed to produce myopathy. Therefore, the regional myopathy produced by the lactate salt provides a model for in vivo cytotoxicity of aluminum in which anionic binding is a critical determinant.
Review Article: Quinolone Arthropathy—Acute Toxicity to Immature Articular Cartilage
Authors: Gough Alec W. , Kasali Olajide B. , Sigler Robert E. , Baragi Vijaykumar
Published: April 2009

A class effect of quinolone antibacterial agents observed during animal toxicity testing is a specific arthropathy (QAP). Despite the growing list of laboratory animals susceptible to QAP and reports of arthralgia in patients treated with quinolones, the potential for QAP development in humans remains unknown. This review discusses current concepts in the biology of articular cartilage and how these concepts elucidate QAP pathogenesis. Biomechanical forces within synovial joints and toxicokinetic properties of quinolones contribute to QAP induction. Since a limited number of mechanistic pathways exist for acute articular damage, QAP may serve as a research tool to probe the pathobiology of injury to articular cartilage.
The Histology and Development of Hepatic Nodules and Carcinoma in C3H/He and C57BL/6 Mice Following Chronic Phenobarbitone Administration
Authors: Evans John G. , Collins Michael A. , Lake Brian G. , Butler William H.
Published: April 2009

Male C3H/He and C57BL/6 mice were given diets containing sodium phenobarbitone (PB) to allow a daily intake of 85 mg/kg. Control and treated animals were killed at 5, 30, 40, 60, and 80 wk. Other mice were killed in extremis or at the end of the respective experiments: 91 wk for C3H/He and 100 wk for the C57BL/6 animals. A basophilic nodule was found in 1/5 control C3H/He mice at 30 wk; these nodules increased in number with time so that nodules of this type were found in approximately 70% of animals by 91 wk. Nodules were not found in control C57BL/6 mice until 80 wk, when they were found in 4% of mice. PB treatment markedly increased the number of hepatic nodules in both strains of mice. The additional nodule burden was due to the development of a second nodule type formed of large cells with a predominantly eosinophilic cytoplasm. C3H/He animals given PB for 60 wk and then returned to a control diet bore fewer nodules at 91 wk than treated mice killed at 60 or 91 wk. The cumulative incidence of carcinoma in control C3H/He and C57BL/6 mice was 28 and 4%, respectively. The incidence of carcinoma was not increased by PB treatment in either strain. It is concluded that both strains of mice behave in a qualitively similar way to PB administration, although they show considerable quantitative differences in terms of the time and number of nodules that develop. Furthermore, the increased nodule numbers associated with PB treatment were not accompanied by an increase in the number of carcinomas.
General Responses of the Bone Marrow to Injury
Authors: Rebar Alan H.
Published: April 2009

Hematologic responses in a toxicologic setting may be quite complex and may involve both local as well as systemic manifestations of toxicity and/or pharmacologic response. Direct toxicity to bone marrow can lead to changes such as marrow necrosis, marrow dysplasia, and macrophage hyperplasia. Some toxic compounds can directly stimulate or suppress the development of 1 or more marrow cell lines. The marrow may also respond to injury at distant sites with increased production of various blood cell elements. Accurate interpretation of hematologic responses generally involves integration of peripheral blood data with bone marrow findings as well as toxicologic findings in other organ systems. This manuscript overviews the various marrow changes encountered in toxicologic studies and provides a perspective of how these changes are best approached from an interpretive viewpoint.
Principles of Hematotoxicology: Laboratory Assessment and Interpretation of Data
Authors: Bloom John C.
Published: April 2009

The toxicologic evaluation of the hematopoietic system is part of most preclinical and clinical safety studies and has become routine in monitoring a variety of novel and conventional therapies in humans and animals. As with spontaneous disease, iatrogenic blood dyscrasias may be primary but are frequently secondary to other tissue toxicity. The latter tendency makes this easily accessible tissue particularly useful in monitoring for systemic toxicity, while primary hematotoxicity ranks with liver and kidney effects as important and often limiting complications. Although the principles driving the diagnostic approach to spontaneous (clinical) blood disorders generally apply to preclinical and clinical safety studies, there are important differences, particularly regarding control of variables, feasibility of testing, and interpretation of resulting data. The luxury of studying a homogenous population of subjects free of complicating disease under controlled (uniform) laboratory and environmental conditions allows changes to be defined with greater precision and sensitivity. There are generally more options regarding the assays available and frequency of monitoring. Moreover, the hierarchy of tests applied are influenced by regulatory as well as scientific or problem-driven indications. Finally, interpretation of laboratory findings is usually based on the use of subjects as their own controls (pretreatment and sequential monitoring), comparison to a control population and well-defined reference ranges specific for the population under study, and in accordance with the principles of pathology and internal medicine.
Retrovirus-Induced Lymphoproliferation as a Model for Developing Diagnostic Criteria for Malignant Lymphoma in Mice
Authors: Fredrickson Torgny N. , Yao Tang  , Chattopadhyay Sisir K. , Morse Herbert C. , Hartley Janet W.
Published: April 2009

Several methods for evaluating lymphoproliferative lesions in mice were compared. The model systems included spontaneous lymphomas arising in CWD mice and NFS mice congenic for ecotropic murine leukemia virus (MuLV) induction loci and a series of transplants in mice with severe combined immunodeficiency disease mutation of cells derived from mice infected with LP-BM5 MuLV. Primary lymphomas and donor tissues and transplants were examined using histopathology, flow cytometry, and Southern blot analysis of DNA for rearrangements of immunoglobulin and T-cell receptor genes and for viral integrations. The use of flow cytometric analysis, to establish cell lineage and define population size, and DNA analysis, for cell lineage and clonality determination, allowed the identification of malignant lymphoproliferations. Histologic evaluation did not define clonal populations of particular lineage but did provide other indications of malignancy such as invasiveness and presence of a dominant morphologic cell type. Thus, the precision of diagnosis of mouse lymphomas can be considerably enhanced by augmenting histopathologic examination with antigenic and molecular characterizations that can define malignant populations.
Cytokine Technology in Basic and Applied Research on the Hematopoietic System
Authors: House Robert V.
Published: April 2009

Cytokines are polypeptide molecules important for the regulation and maintenance of immunity and hematopoiesis. Their central role in the control of a number of physiological mechanisms makes them an important area of both basic and applied biomedical research. This review presents an overview of basic and applied biology, and introduces the term cytokine technology to denote the use of cytokines as research tools for understanding the cellular and molecular regulation of hematopoiesis. A number of frontier technologies are reviewed, including fusion toxins, fusion proteins, and animal models of cytokine expression and regulation.
Induction of the Renal Peiyic and Ureteral Carcinomas by N-Butyl-N-(4-Hydroxybutyl)nitrosamine in SD/cShi Rats with Spontaneous Hydronephrosis
Authors: Mori Satoru , Hosono Motoko , Machino Setsuko , Nakai Sachiko , Makino Susumu , Nakao Hiroyuki , Takeuchi Yasuyoshi , Takeda Reiji , Murai Takashi , Fukushima Shoji
Published: April 2009

We attempted to establish an animal model for renal pelvic and ureteral carcinomas. In Experiment 1, Sprague-Dawley (SD)/cShi and SD/gShi strains of male and female rats and Fischer-344 (F-344) DuCrj and LEW/Crj strains of male rats, 6 wk old, were given 0.05% N-butyl- N-(4-hydroxybutyl)nitrosamine (BBN) for 12 wk and then treated without chemical for 10 wk. Only the SD/cShi strain. which has spontaneous hydronephrosis and hydroureter, showed high incidences of carcinomas in the renal pelvises and ureters, whereas the other strains did not. In Experiment 2, SD/cShi and Crj:CD strains of male and female rats. 6 wk old, were exposed to 0.05% BBN for 20 wk. Both sexes of SD/cShi rats had high incidences of bilateral carcinomas in renal pelvises and/or ureters associated with urinary bladder carcinomas, whereas both sexes of Crj:CD rats had urinary bladder tumors only. These results indicate that the SD/cShi strain may be a suitable animal for the induction of renal pelvic and ureteral carcinomas that appear to depend on urine stagnation secondary to hydronephrosis and hydroureter.
Interleukin-la Reduces the Severity of the Vascular Leak Syndrome Produced by Interleukin-2 and Interleukin-2 Plus Interferon-a
Authors: Fujita Shinsuke , Puri Raj , Yu Zu-Xi , Travis William , Yamaguchi Maria , Ferrans Victor J.
Published: April 2009

Histological and ultrastructural changes were investigated in lung, liver, and heart of mice given interleukin-2 (IL-2), either alone or in combination with other cytokines. IL-2 induced a vascular leak syndrome (VLS) of a moderate degree with infiltration of lymphoid cells, moderate endothelial damage. mild hepatic parenchymal damage, and minimal myocardial alterations. Interferon-a (IFN-α) produced infiltration mainly of monocytes/macrophages in liver and heart; endothelial cell damage was absent in lung and heart and minimal in liver. Interleukin-1α (IL-1α) caused an increased number of neutrophils in liver and lung; VLS and parenchymal cell and endothelial damage were not found. The VLS and the cellular damage caused by the combination of IL-2 and IFN were much more severe than those produced by IL-2 alone. In animals treated with IL-2, IFN-α, and IL-1α, VLS was minimal and parenchymal and endothelial cell damage were less severe than after IL-2 alone or IL-2 plus IFN-α. Taken together, these observations show that IL-1α reduces ultrastructural changes produced by IL-2 and IFN-α. This reduction may be clinically useful in the treatment of neoplasms.
Atypical Tubule Hyperplasia and Renal Tubule Tumors in Conventional Rats on 90-Day Toxicity Studies
Authors: Hard Gordon C. , Long Philip H. , Crissman James W. , Everitt Jeffrey I. , Yano Barry L. , Bertram Timothy A.
Published: April 2009

Bilateral, multicentric renal tubule tumors were found in 4 rats at the termination of 3 separate 90-day toxicity studies during the safety evaluation of 3 unrelated chemicals. The 3 studies were conducted at 2 separate locations, but the rats used were obtained from the same commercial source. The rat strains were Fischer-344 (1 male and 1 female case) and Sprague-Dawley (2 female cases). Three of the renal tumor cases were from either the high-dose or mid-dose treatment groups, and 1 case was an untreated control. The tumors were accompanied by multiple foci of atypical tubule hyperplasia but only in the tumor-bearing rats. There were no lesions associated with renal tumor pathogenesis in any of the remaining treated or untreated animals in the 3 studies. In addition, there was no indication of nephrotoxicity in the treated or untreated animals. Tumor morphology was characterized by a generally vacuolated appearance, eosinophilia, cytoplasmic and nuclear pleomorphism, and conspicuously hypertrophied nucleoli. The renal tubule tumors in these 90-day studies were compared to hereditary renal tubule tumors occurring in the Eker rat, a Long-Evans derivative with a genetic predisposition to this tumor type. The multiplicity of renal tubule tumors, early age of onset, and tumor morphology described in the cases from the 90-day studies were very similar to those characterizing the hereditary renal tumor model. The following evidence demonstrates that the 4 cases of renal tubule tumor developing in young rats in the course of 90-day studies were of spontaneous origin and not compound-induced: the tumors could not be reproduced by the test compound in a repetition of the 90-day toxicity study in which 2 of the cases occurred; pertinent renal lesions, including atypical hyperplasia, were seen only in tumor-bearing rats; there was an absence of nephrotoxicity in any of the treated rats and an absence of a dose-response relationship for the observed kidney alterations; 1 case was found in an untreated rat. The striking similarity of the tumors in these 4 cases to hereditary renal tumors occurring spontaneously in Eker rats suggests that the 90-day kidney alterations described here may be compatible with a genetic defect. As an alternative explanation, the possibility of a viral etiology was also considered.
Morphology and Incidence of Hepatic Foci of Cellular Alteration in Sprague-Dawley Rats
Authors: Newsholme Stephen J. , Fish Colin J.
Published: April 2009

Morphology and incidence of altered hepatocellular foci (AHF) were evaluated in standard H&E-stained liver sections from 3 groups of control Sprague-Dawley (SD) rats (initially 70/sex/group) used in 2 2-yr carcinogenicity studies. All AHF observed could be classified as basophilic, eosinophilic, clear, vacuolated, or mixed types using criteria applied previously to the Fischer-344 (F-344) rat. Some eosinophilic foci were large and posed a diagnostic challenge in differentiation from hepatocellular adenoma. Rats were arbitrarily divided into 3 classes by age at death: 14-17, 18-23, and 24-26 mo. As reported for F-344 rats, the incidence of SD rats with AHF increased with age, and males with eosinophilic foci predominated over males with basophilic foci whereas the opposite held true for females. Mean incidence of rats with AHF at 18-23 mo was 28 and 38% for males and females, respectively, and at 24-26 months was 68 and 71%, respectively. These data indicate a strikingly lower incidence of spontaneous AHF in SD rats than that reported for F-344 rats.
Comparative 90-Day Feeding Study with Low-Viscosity White Mineral Oil in Fischer-344 and Sprague-Dawley-Derived CRL:CD Rats
Authors: Firriolo Janet M. , Morris C. Fred , Trimmer Gary W. , Twitty Linda D. , Smith Jacqueline H. , Freeman James J.
Published: April 2009

A 90-day study was conducted to compare the effects of dietary administration of a food-grade white oil in female Fischer-344 (F-344) and Sprague-Dawley-derived (CRL:CD) rats. Animals were fed a low viscosity (15 mm2/sec at 40°C) paraffinic white oil (designated as P 15[H]) at 0, 0.2, or 2.0% of the diet for 30, 61, or 92 days. There were no significant adverse clinical observations or unscheduled deaths. In the F-344 rats, occasional treatment-related changes were seen in hematology and clinical chemistry parameters. At necropsy, mesenteric lymph nodes were enlarged, and there was an increase in absolute and relative liver, mesenteric lymph node, and spleen weights as compared to controls. Histopathologic effects included hepatic and mesenteric lymph node microgranulomas and mesenteric lymph node histiocytosis. In CRL:CD rats, the only effects noted were accumulations of chronic inflammatory cells in the liver at the high dose only, without the formation of discrete microgranulomas. A dose-related increase in mineral hydrocarbon (MHC) material in the liver and mesenteric lymph nodes was observed in both F-344 and CRL:CD rats. Although increased, liver MHC content was significantly less (approximately 50%) in CRL:CD rats than the levels detected in the F-344 rats. Mesenteric lymph node MHC levels did not differ significantly between the strains. This study demonstrated strain differences among rats in histopathologic effects of white oil, with the CRL:CD rat essentially showing no response compared to the F-344 rat. The differences in the pathologic responses between the 2 strains appears to result from the higher MHC tissue content and a greater sensitivity of the F-344 rat to the presence of the MHC material.
Toxicokinetics/Toxicodynamic Correlations: Goals, Methods, and Limitations
Authors: Batra Vijay K.
Published: April 2009

Toxicokinetic (TK) studies are the basis for demonstrating dose-related drug exposure in animals and for ensuring that drug exposure is substantially greater in animals than that expected in humans at therapeutic doses. The usefulness of TK studies can be further enhanced by correlating TK parameters with relevant toxicologic end points. The so-called TK/toxicodynamic (TD) correlations can be extremely useful in bridging data from studies both within and across species and in designing early Phase I clinical trials. These correlations assume that toxicologic responses are comparable among species at comparable plasma concentrations. This assumption may apply for certain drugs but not for others. Therefore, TK/TD correlations should be developed and utilized on a case-by-case basis. Such correlations have proven to be extremely useful with anticancer drugs in formulating dose escalation strategies in cancer patients to rapidly attain the maximum tolerated and/or effective dose. However, these correlations have not been utilized effectively in other therapeutic areas. The development of TK/TD correlations, their scope, and limitations are discussed in this paper.
Preclinical Drug Metabolism Programs for Food-Producing Animals
Authors: Clement Robert P.
Published: April 2009

To register a new veterinary drug for use in food-producing animals, the sponsor must demonstrate that drug-related residues in the edible tissues (liver, kidneys, muscle, fat, and milk or eggs) of treated animals are safe when consumed by humans. The sponsor must develop information on the amount, persistence, and chemical nature of the drug-derived residue in the edible tissues in order to ensure safety. This information is compared to that on the metabolism and toxicity of the compound in the laboratory animal species used for the toxicity evaluation. The toxicity data is utilized to establish the safe concentration of drug-related residue in the edible tissues. An estimate of the safe concentration is necessary to proceed with residue studies that will adequately determine the rate of depletion of total residue over the projected range of probable safe concentrations. Appropriate study design requires close communication among the toxicologist, pathologist, and residue chemist. The safe concentration of total residue and residue depletion profile are used to determine the withdrawal period for the veterinary product. The required studies, including design and timing, will be discussed.
Food and Drug Administration Viewpoints on Toxicokinetics: The View from Review
Authors: Degeorge Joseph J.
Published: April 2009

The importance of drug kinetics for interpretation of toxicity findings and for cross-species toxicity assessment has been long recognized. Recently, an international effort was initiated to standardize guidance on the kinetic data to be collected in conjunction with toxicity studies. The guidance addresses the kinetic data to be included in studies on carcinogenicity, reproduction toxicity, genotoxicity, and single- and repeat-dose toxicity. In various stages of development or implementation, the guidance is intentionally nondetailed regarding the specific kinetic assessments to be performed. This is to allow flexibility in study design and ensures that scientific judgment is used to determine the appropriate kinetic endpoints to achieve study- and drug-specific goals. Some examples of how kinetics have been used at the Food and Drug Administration in review of toxicity studies submitted in drug applications are presented. The examples discussed demonstrate successful and unsuccessful integration of kinetics into study design and interpretation and highlight the impact on the drug development program from a regulatory perspective.
Disturbance of Macrophage and Monocyte Function in the Dog by a Thromboxane Receptor Antagonist: ICI 185,282
Authors: Westwood F. Russell , Duffy Paul A. , Malpass Debbie A. , Jones Huw B. , Topham John C.
Published: April 2009

ICI 185,282 is a specific thromboxane receptor antagonist developed by ZENECA Pharmaceuticals for potential use in the treatment of inflammatory disease. During safety evaluation in dogs, multifocal granulomatous infiltrates occurred in multiple organs at high dose levels. These consisted predominantly of enlarged histiocytic cells. We report a 28-day investigative study in which Millipore filters overlaid with carbon were implanted subcutaneously. Histological assessment of the developing foreign body granulomatous tissue response and evaluation of in vitro migration of peripheral blood monocytes were performed. The development of epithelioid macrophages with altered behavior, modification of fibroplasia, and increased monocyte infiltration at the implant site resulted from administration of ICI 185,282. This was accompanied by enhanced migration of isolated peripheral blood monocytes in vitro. We believe that the granulomatous infiltrates that occurred during toxicological assessment in dogs may be a result of a drug-induced disturbance in macrophage response to concurrent subclinical inflammations or alteration in the normal disposition of tissue macrophages, i.e., they were a result of an atypical response to a concurrent stimulus for macrophage activity.
Histological Examination on Achilles Tendon Lesions Induced by Quinolone Antibacterial Agents in Juvenile Rats
Authors: Kato Michiyuki , Takada Sanae , Kashida Yoko , Nomura Mamoru
Published: April 2009

We examined the effects of the quinolone antibacterial agents pefloxacin (PFLX) and ofloxacin (OFLX) on the Achilles tendon of Sprague-Dawley rats. A single oral administration of PFLX 300 and 900 mg/kg or OFLX 900 mg/kg induced edema with mononuclear cell infiltration mainly in the inner sheath of the inner Achilles tendon just proximal to the tuber calcanei in rats killed on the next day. Cell infiltration was also seen in the adjacent synovial membrane and joint space. With progression of severity, the lesions extended to the surface tendon tissue, wherein irregularly arranged collagen bundles were detached from each other and nuclei of fibroblasts were pyknotic and fragmented. After 2-wk repeated administration, these lesions were replaced by fibrotic foci with regenerated tendon fibroblasts, and the incidence and severity were reduced in the OFLX but not PFLX groups. Coadministration of cyclosporin A with OFLX 300 mg/ kg induced these lesions despite the fact that neither induced lesions alone. The tendon lesions were induced in juvenile rats (4 wk of age) but not in young adults (12 wk). The articular cartilage of juvenile rats showed focal degeneration and/or cavitation in the tarsal joints after a single and 2-wk administration of PFLX or OFLX. Hydrocortisone slightly increased the incidence of OFLX-induced lesions in both the tendon and cartilage after a 2-wk administration. The occurrence of the tendon lesions is different from that of the Achilles tendon disorders reported in older humans, but they are thought to be a useful model for them.
Comparison of Acute Hepatocellular Proliferating Cell Nuclear Antigen Labeling Indices and Growth Fractions, p34cdc2 Kinases, and Serum Enzymes in Carbon Tetrachloride-Treated Rats
Authors: Monticello Thomas M. , Barton Debra , Xinfang Ma  , Babish John G. , Durham Stephen K.
Published: April 2009

We evaluated various biomarkers associated with cell proliferation immediately following insult with the classic hepatotoxicant carbon tetrachloride (CCl4). Rats were administered a single necrogenic dose of CCl4 and euthanized at either t = 4, 8, 12, 16, or 24 hr postdose. Parameters evaluated included the following: immunohistochemical detection of hepatocellular proliferating cell nuclear antigen labeling indices (PCNA-LIs; percentage of cells in S phase) and growth fractions (PCNA-GFs; percentage of cells in the cell cycle); PCNA and the cyclin-dependent kinase p34cdc2 (CDK) protein in S-9 fractions by Western blot and enzyme-linked immunosorbent assay (ELISA); and liver-related serum enzymes. An increase in PCNA-GF was observed at t = 4 hr, concomitant with elevations in CDK and PCNA protein (Western blot). PCNA-LIs were increased by t = 24 hr, as were CDK and PCNA by ELISA. Sorbitol dehydrogenase was the most sensitive enzyme, with increases observed at t = 4 hr. Our results indicate that PCNA-GF, CDK, and PCNA levels reflect hepatocellular regeneration as early as 4 hr following CCl4 insult. We conclude that these assays are early and sensitive indicators of acute hepatotoxicity that may be advantageous to evaluate in the early stages of exploratory studies.
1,3,5-Trinitrobenzene-Induced Encephalopathy in Male Fischer-344 Rats
Authors: Sundeep Chandra A.M. , Qualls Charles W. , Reddy Gunda
Published: April 2009

Administration of 1,3,5-trinitrobenzene (TNB) to male Fischer-344 rats produced ataxia after 6 or 7 oral doses (71 mg/kg). Light microscopic examination after 10 days revealed petechial hemorrhages in the brain stem and cerebellum and bilaterally symmetric degeneration and necrosis (malacia) with reactive gliosis in the cerebellar peduncles. The malacia was dorsal and lateral to the fourth ventricle involving the cerebellar nuclei, medial and lateral vestibular nuclei, and inferior colliculi. Blood vessels associated with the lesion had widened Virchow-Robin spaces, occasionally with extravasated erythrocytes. Rats administered daily oral doses of 35.5 mg/kg of TNB for 10 days and 35.5 and 71 mg/kg of TNB for 1 or 4 days did not have brain lesions.
Rapid Induction of Preneoplastic Liver Foci in Embryonal Turkey Liver by Diethylnitrosamine
Authors: Enzmann Harald , Kühlem Christiane , Kaliner Georg , Löser Eckhard , Bannasch Peter
Published: April 2009

Diethylnitrosamine (DEN) was injected into fertilized turkey eggs. After incubation for 24 days, the livers of the embryos were removed and investigated by means of histological and enzyme-histochemical methods. Doses of 2 and 5 mg DEN per egg had no effect on mortality and embryo weight but induced various types of foci of altered hepatocytes. In addition, a replacement of the trabecular structure of the liver by a tubular arrangement of the hepatocytes and markedly enlarged hepatocytes were found. The diethylnitrosamine-induced foci of altered hepatocytes were very similar to the preneoplastic lesions that occur in the liver of mammals during hepatocarcinogenesis and are regarded as early indicators of carcinogenicity. The presented in ovo model is a simple (1 dose), rapid (24 days), and inexpensive (no animal housing) approach for the induction of foci of altered hepatocytes. The sensitivity of this carcinogenesis bioassay appears to be comparable to that of lifetime studies in rodents. It is proposed that the induction of preneoplastic foci of altered hepatocytes in ovo is a valuable screening model for hepatocarcinogenic effects.
Problems in Consideration of Rodent Hepatocarcinogenesis for Regulatory Purposes*t
Authors: MocH Ronald W. , Dua Prem N. , Hines Fred A.
Published: April 2009

Hepatoproliferative lesions of rodents are frequently reported in petitions containing pathology data from chronic toxicity and carcinogenicity studies submitted to the Center for Food Safety and Applied Nutrition of the Food and Drug Administration. The Pathology Branch of the Office of Scientific Analysis and Support evaluates these data, which are submitted in support of the safe use of food additives, color additives, and other regulated products. Data are reviewed for the adequacy of the information provided, the terminology used to describe the reported lesions, and the overall scientific rationale used in interpreting the biological significance of the observed lesions. When questions arise during the review process, additional data, information, or clarification are sought from the petitioner. Microslides may be requested from the petitioner so that an independent evaluation of the lesions may be conducted. Several examples of recent evaluations of hepatoproliferative lesions are presented to illustrate some of the problems encountered during the review process and to demonstrate the procedures and approaches used in the evaluation of hepatocellular lesions within the center.
Effects Found in a One-Year Oral Toxicity Study in Sprague-Dawley Rats of a Novel 5-HT1A Receptor Partial Agonist for the Treatment of Anxiety in Humans
Authors: Zwicker G.M. , Gosselin S.J. , Solomon J.L. , Hurst G.H.
Published: April 2009

A potent and selective serotonin (5-HT1A) partial agonist with potential as a human anxiolytic drug was given in oral doses of 0, 5, 15, or 50 mg/kg/day by gavage to Sprague-Dawley rats for 6 or 12 mo. Some animals were allowed 1 mo to recover after each treatment period. The 10-fold increase in dose resulted in a 20-fold increase in drug plasma concentration due to saturable first-pass metabolism. This resulted in disproportionately higher concentrations and greater bioavailability of the 15- and 50-mg/kg/day regimens. Drug exposure was associated with decreased spontaneous activity in the 15- and 50-mg/kg rats. The activity of these rats returned to normal during the recovery period. There were significant (p < 0.05) decreases in mean body weights during the study for 50-mg/ kg males, with improvement during the recovery periods. No biologically significant effects were noted in clinical laboratory parameters. Based on organ weight increases and histopathological evaluation, drug-related effects after 6 and 12 mo of treatment were in the pituitary (both sexes) and all treated female reproductive organs. In general, these effects persisted into periods of recovery, except for pituitary hyperplasia, which was not apparent following recovery after treatment for 6 mo. After treatment for 12 mo and the following recovery, there were significant increases in adrenal weights in the 15- and 50-mg/kg/day males with no morphological correlate. There was increased pituitary hyperplasia that persisted through the recovery period in all treated groups in both sexes, but there was no increase in pituitary neoplasms. In treated females, there was also morphologic evidence of persistent diestrus (estrogenic effect) evidenced by endometrial squamous metaplasia, increased corpora lutea, vaginal mucification, and decreased uterine size. The clinical and pathological changes seen with these 2 regimens were considered exaggerated pharmacological effects of the drug on serotonin receptor-rich organs.
Brief Communication
Authors: Shibuya Kazumoto , Tajima Masanori , Nunoya Tetsuo
Published: April 2009

A spontaneous tumor in the nasal cavity, extending through the cribriform plate to the cranial cavity, was detected in a 103-wkold female Fischer-344/DuCrj rat. The tumor appeared to arise from the olfactory epithelium and was composed of round to polygonal, undifferentiated cells arranged in solid sheet-like and lobular patterns with scant fibrovascular stroma. Ultrastructurally, the tumor cells often formed desmosomes between contiguous cells and had no neurosecretory granules. Immunohistochemically, the tumor cells did not react with any antibodies specific for intermediate filaments, neuronal, muscular, and endothelial elements. Based on these results, the tumor was diagnosed as undifferentiated olfactory epithelial carcinoma.