bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting the Future: How Affect-Related Personality Traits Influence Likelihood Judgments of Future Events
Authors: Zelenski John M. , Larsen Randy J.
Published: April 2009

The authors examine the possibility that personality traits linked to positive and negative affect susceptibilities also influence performance on a mood-sensitive cognitive task: likelihood judgments of possible positive and negative future events. In Study 1, participants (n = 104) filled out personality questionnaires, rated their current mood states, and rated the likelihood that positive and negative future events would occur. Results confirmed the hypothesis that affect-related traits predict likelihood judgments. Moreover, the personality effects were not mediated by current mood states. A second study (n = 81) replicated these personality effects on judgment in the context of manipulated moods (positive, sad, fearful, and neutral). As in Study 1, personality effects on judgment were not mediated by mood states. The authors suggest that the traits of extraversion and neuroticism include stable cognitive structures that can bias judgment in affect-congruent directions.
Debating with muzzled mouths: a case analysis of how control works in a Chinese television debate used for educating youths
Authors: Zhong Yong
Published: April 2009

This article contains a case analysis of the Biannual International Mandarin Intervarsity Debating Competition jointly staged by China Central Television as a new genre of what I regard as enhanced propaganda. The analysis has been informed by a brief examination of the history of the genre, which invites attention to its importance as a symbol of both China’s cultural superiority and its progress towards democracy and freedom of speech. However, the analysis has found that, under the disguise of its symbolism, the genre is subjected to very strict controls. The case analysis categorized four heuristic types of control, which I call content control, procedural control, semiotic control and interpretative control. The findings of the analysis, to be discussed in this article, will show how the various types of control are intended to eliminate alternative messages in what is seemingly an improvised show. This, I hope, will contribute to a challenge of the popular perception that Chinese television has been liberalized.
Consensus behind disputes: a critical discourse analysis of the media coverage of the right-of-abode issue in postcolonial Hong Kong
Authors: Pan Xiaping
Published: April 2009

This article examines the reportage by four newspapers on the right-of-abode issue in postcolonial Hong Kong, in an attempt to analyze how the same new events might be framed by different ideologies, resulting in different coverage. The coverage is first approached through the analysis of lexical choices, followed by propositional analysis. A discussion section is intended to interpret those differences, in terms of the selectiveness of the newspapers, in light of Simpson’s definition of ideology. The conclusions drawn from the previous analyses are finally tested by corpus analysis, which lends further support to the preceding text analysis. This article intends to emphasize that, behind the differences in coverage, there is consensus, that is, news coverage is closely in line with its underlying ideological positions, which is instantiated politically, culturally and institutionally.
Political clientelism and the media: southern Europe and Latin America in comparative perspective
Authors: Hallin Daniel C. , Papathanassopoulos Stylianos
Published: April 2009

This article explores the relationship between political clientelism and the development of media systems in southern Europe and Latin America, considering the cases of Greece, Italy, Spain, Portugal, Mexico, Colombia and Brazil. Common characteristics of the media systems in these countries include low newspaper circulation, a tendency towards political instrumentalization of the media, limited development of journalism as a differentiated and autonomous profession, and regulatory agencies that are at the same time party-politicized and relatively weak. We argue that these media-system characteristics must be understood in relation to a broader history of political clientelism - though a number of forces, including commercialization of media industries and globalization, have tended in recent years to undermine clientelistic relationships.
The return of the National Union of Journalists to the provincial newspaper industry in Britain?
Authors: Gall Gregor
Published: April 2009

This article examines whether the National Union of Journalists (NUJ) can regain its former position of industrial influence within the British provincial newspaper industry after a decade of de-recognition by employers, particularly in the context of the new statutory mechanisms to gain union recognition. The article outlines the process by which the NUJ was de-recognized by employers and demonstrates how the union has made considerable progress in regaining recognition rights after maintaining its membership base. However, it concludes that such progress is not necessarily synonymous with rebuilding its organizational presence and influence given continuing employer hostility and membership weakness.
Ideal types in public service television: paternalists and bureaucrats, charismatics and avant-gardists
Authors: Ytreberg Espen
Published: April 2009

Over time, the broadcast media develop conventions of self-presentation that are formulated more or less explicitly by academics and media professionals as ideal types. The article discusses four such ideal types of self-presentation in television: paternalists and bureaucrats, charismatics and avant-gardists. It demonstrates how they have been formulated and evaluated by researchers and media professionals. Following Raymond Williams’s notion of ‘dominant’, ‘residual’ and ‘emergent’ forms, the article also discusses the historical interactions and contests between them. Examples are drawn from Nordic and British public service broadcasting. A case is made for acknowledging the coexistence of several ideal types, rather than taking at face value notions of some general ‘slide’ from a paternalist past to a charismatic present. The article draws particular attention to the importance of bureaucratic modes of self-presentation for understanding early public service television, and of avant-gardist modes for understanding more recent developments.
Informational uses of spiritual information: an analysis of messages reportedly transmitted by extraphysical means
Authors: Kari Jarkko
Published: April 2009

This article explores informational uses of spiritual information presented in spiritual publications. Informational use entails cognitive or communicational activity that — on the basis of information — focuses on representations of the perceived existence, whereas practical use of information centres on tangible — material or energetic — activities of the real world. Some earlier research has been done on the informational uses of information, but spiritual information has been ignored almost altogether in this context. The empirical work was grounded on a representative sample of spiritual texts. The method of analysing the data was inductive content analysis. The main result of this study was the discovery and dissection of three fundamental varieties of informational information use: internalizing information, processing knowledge, and externalizing knowledge. The classification constructed in this study can be seen as a useful tool for further investigation into information use, but it should be refined in subsequent research.
Recombinant Human Soluble CD4 Does Not Inhibit Immune Function in Cynomolgus Monkeys
Authors: Bugelski Peter J. , Thiem Patricia A. , Truneh Alemseged , Morgan D. Gwyn
Published: April 2009

Recombinant soluble CD4 (sT4) has been shown to inhibit infectivity of HIV. Because of the role CD4 plays in the interaction of T-helper lymphocytes and cells bearing MHC Class II antigens, a potential adverse effect of therapy with sT4 is interference with lymphocyte function. To address this issue, we studied the effects of sT4 on mitogen-mediated blastogenesis, mixed lymphocyte reactions, and delayed type hypersensitivity reactions (DTH) in cynomolgus monkeys. We found no evidence of sT4-mediated suppression on the in vitro response to concanavalin A, phytohemagglutinin or pokeweed mitogen in 2-way mixed lymphocyte reactions, either when sT4 was added to the cultures or when cells were obtained 3 hr after drug administration from animals that received up to 100 mg/kg as an intravenous bolus. Furthermore, we also found no effect of sT4 on lymphocyte subsets or on the ability of monkeys to respond to dinitrochlorobenzene (DNCB)-mediated DTH. Because of the high degree of conservation of CD4 and MHC Class II antigens across the macaque-human barrier, these data suggest that soluble CD4-like molecules are unlikely to be immunosuppressive in humans.
Abnormal Auditory Brainstem Responses and Cochlear Pathology in Rats Induced by an Exaggerated Styrene Exposure Regimen
Authors: Yano Barry L. , Dittenber Dean A. , Albee Ralph R. , Mattsson Joel L.
Published: April 2009

Groups of 12 male 42-day-old rats were exposed to 0 or 800 ppm styrene vapors for 14 hr/day, 5 days/ week for 3 weeks. Tone-pip auditory brainstem responses (ABRs) at 4, 8, 16, and 30 kHz were obtained after the last exposure. ABRs were minimally affected at 4 kHz and moderately to severely affected at 8, 16, and 30 kHz as indicated by waveforms which had a decreased amplitude and increased latency as compared to the controls. Missing outer hair cell(s) were evident in the basal and lower middle turns of the organ of Corti. Outer hair cell loss was least in the first row and greatest in the second and third rows. Occasional inner hair cells were also missing in regions of severe outer hair cell loss. The distribution of hair cell loss within the cochlea was consistent with the pattern of ABR alterations. These data document mid-frequency auditory dysfunction in styrene-exposed young adult rats with significant damage to the organ of Corti following an exaggerated styrene exposure regimen.
Pathogenesis of Blood-Filled Cavities in Estrogen-Induced Anterior Pituitary Tumors in Male Sprague-Dawley Rats
Authors: Van Nesselrooij Joop H. J. , Hendriksen Ferry G.J. , Feron Victor J. , Bosland Maarten C.
Published: April 2009

The formation of blood-filled cavities in developing tumors of the anterior pituitary of estrogen-treated male Sprague-Dawley rats was studied in a serial sacrifice experiment. Two treated and 2 control rats were killed at each of 15 time points ranging from 7-272 days after sc implantation of an estradiol-17β pellet. The pituitaries were examined using light and electron microscopy. Changes at 7-9 days after implantation included epithelial cell swelling and trabecular arrangement. At 11-13 days, epithelial cells were further enlarged. Arrangement of epithelial cells in islands and endothelial degeneration were first seen at this interval. Also, any sinusoids were distended, whereas some were compressed by swollen epithelial cells. At 16-81 days, scattered necrotic and immature epithelial cells were present, and cell size decreased. Endothelial degeneration and both distended as well as compressed sinusoids were more prominent at this time. Loss of basement membrane was first seen during this interval. At 114-133 days, small hemorrhagic areas partially lined by epithelium were first seen; sinusoidal compression, endothelial necrosis, and loss of basement membrane were more frequent, but there was less sinusoidal distention. Between 150 and 272 days, epithelial cells were increasingly pleomorphic and arranged in nodules, and there was an increase in number and size of the hemorrhagic areas. Sinusoidal compression, endothelial necrosis, and loss of basement membrane were abundant, whereas sinusoidal distention had almost disappeared at this interval. Local compression of sinusoids and perhaps compression of pituitary surface veins due to epithelial cell swelling, were thought to play a primary role in the development of ischemic endothelial damage leading to loss of endothelial lining and basement membrane, and eventually to the formation of blood-filled spaces partially lined by epithelial cells.
The Morphology, Immunohistochemistry, and Incidence of Hematopoietic Neoplasms in Mice and Rats
Authors: Frith Charles H. , Ward Jerrold M. , Chandra Manik
Published: April 2009

Hematopoietic neoplasms in the rodent may be classified into lymphoid or nonlymphoid neoplasms. Lymphoid neoplasms include the following morphologic types: follicular center cell, lymphoblast (lymphocytic), immunoblast, plasma cell, and large granular lymphocyte (LGL). Nonlymphoid hematopoietic neoplasms include histiocytic sarcoma, granulocytic leukemia, erythroid leukemia, and mast cell tumors. Most types of hematopoietic neoplasms, exclusive of LGL lymphoma (leukemia), are more common in mice than in rats. Specific strains of mice have a hematopoietic tumor incidence of more than 50% in aged animals. Some strains of rats (i.e., Fischer-344) may have an incidence of over 50% of LGL lymphoma in aged animals. The tumor type and incidence are characteristic for each rat or mouse strain. Hematopoietic neoplasms have been better characterized immunomorphologically in mice than in rats. The specific cell type and tissue of origin for hematopoietic neoplasms may be important for safety evaluation of chemicals. Specific chemicals may induce specific types of these tumors, which may be the same or different from the spontaneous types. Lymphoid cell neoplasms should not be grouped with nonlymphoid neoplasms in determining the toxicity and carcinogenicity of test substances.
Pathologic Effects of Butylated Triphenyl Phosphate-Based Hydraulic Fluid and Tricresyl Phosphate on the Adrenal Gland, Ovary, and Testis in the Fischer-344 Rat
Authors: Latendresse John R. , Brooks Charles L. , Capen Charles C.
Published: April 2009

Triaryl phosphates including tricresyl phosphate (TCP) and butylated triphenyl phosphates (BTPs) are used in the commercial manufacture of plastics, lubricants, and hydraulic fluids. Recent reports implicate these compounds as endocrine and reproductive toxicants in rodents. The objectives of this study were to develop and characterize a rat model to investigate the mechanism(s) of toxicity of triaryl phosphate-based hydraulic fluids and to elucidate potential mechanistic pathways of toxicity through studies of structural/ functional relationships. Groups of male and female rats received daily oral doses of either sesame oil alone or 1.7 g/kg of BTP or 0.4 g/kg TCP in sesame oil vehicle or 2.8 g/kg neat BTP for 20, 40, and 60 days. Light microscopic, morphometric, ultrastructural, and histochemical studies revealed hypertrophy and cholesteryl lipidosis of adrenocortical (both sexes) and ovarian interstitial cells that were progressive with duration of exposure. Minimal degeneration was observed in the adrenal cortex and ovary. TCP caused the most severe lesions in both the adrenal gland and ovary, but the morphologic and histochemical changes produced were similar for both compounds, suggesting a common mechanism of toxicity. Decreased testicular weight and degeneration of seminiferous tubules were detected only in TCP-treated rats. The Fischer-344 rat model using TCP and BTP administered by gavage is a valuable system to study mechanisms of endocrine and reproductive toxicity induced by triaryl phosphate-based hydraulic fluids.
Goals, Design, Timing, and Future Opportunities for Nonclinical Drug Metabolism Studies
Authors: Miwa Gerald T.
Published: April 2009

The nonclinical ADME (adsorption, distribution, metabolism, and excretion) studies employed during drug development are dependent on the regulatory expectations and the changing development focus from nonclinical to clinical issues. These evolving issues necessitate that the development goals for ADME studies also change during the development process. The rationale for these goal changes and their impact on the timing and design of the ADME studies are discussed in the context of drug development at Glaxo Inc. The progress in the technology and knowledge in drug metabolism and in biology provide new opportunities for pharmaceutical companies in predicting drug toxicities relevant to humans. Two case examples are discussed to illustrate this opportunity.
Age-Related Neoplasia in a Lifetime Study of Ad Libitum-Fed and Food-Restricted B6C3F1 Mice
Authors: Sheldon Winslow G. , Bucci Thomas J. , Hart Ronald W. , Turturro Angelo
Published: April 2009

Longevity, body weight, and age-specific neoplasia were determined in 1,064 B6C3F1 mice as part of a coordinated study of food restriction (FR). Restricted animals were offered 60% of the diet consumed by the ad libitum (AL) group. Longevity data were derived from a set of 56 animals of each sex from each diet group, which were examined whenever dead or moribund. For cross-sectional data, a parallel set of 210 animals were sacrificed in groups of 12-15 at 6-mo intervals. Lifetime body weight was reduced in the FR mice approximately proportional to restriction (i.e., 40%). Food restriction increased the age at 50% survival (median) by 36% in both sexes and increased the maximal lifespan (mean age of oldest 10%) by 21.5% in males and by 32.5% in females. In 56 males of the longevity groups, there were 89 neoplasms in the AL subgroup versus 53 in FR; 56 AL females had 100, versus 58 in 55 FR females. Increase in lifespan of the restricted animals was achieved primarily by decrease in incidence and delay of onset of fatal tumors, of which lymphoma was the most prominent. This report catalogs all of the neoplasms (1,103) observed in longevity and cross-sectional groups, by diet, sex, and age. These data add to the existing knowledge base needed for future studies of dietary restriction and aging as well to evaluate nutrition of animals used in bioassays.
The Pharmacologic Basis of the Cardiovascular Toxicity of Minoxidil in the Dog
Authors: Mesfin Gebre M. , Robinson Franklin G. , Higgins Michael J. , Zhong Wei-Zhu , Ducharme Donald W.
Published: April 2009

Minoxidil (MNX), like several other vasoactive drugs, causes cardiovascular toxicity in dogs by undetermined mechanisms. We studied the mechanism of cardiovascular toxicity of MNX [an adenosine triphosphate (ATP)-sensitive potassium channel opener] by blocking its pharmacologic effects with glyburide (an ATP-sensitive potassium channel blocker) in groups of 5 female beagle dogs treated orally for 2 days with 1.0 mg/ kg/day of MNX alone or with glyburide given in 5 or 6 divided doses of 300 mg/kg at 2 hr before and after each dose of MNX and at 3-6-hr intervals thereafter. A third group of 5 dogs received glyburide alone in the same dosing regimen as in the combination group. Mean arterial pressure (MAP), heart rate (HR), the pharmacokinetics of MNX, and gross and microscopic changes in the heart were evaluated. Glyburide did not influence the pharmacokinetics of MNX but prevented or markedly attenuated the MNX-induced cardiovascular lesions (right atrial hemorrhagic lesions, subendocardial necrosis, or coronary arteritis) occurred in dogs whose MNX-induced hemodynamic effects were effectively blocked by glyburide. In conclusion, the cardiovascular toxicity of MNX in dogs is not caused by a direct toxic effect of MNX on the heart but apparently is related to the exaggerated pharmacologic/profound hemodynamic effects it elicits in the dog.
Suppression of the Hydrazine-Induced Formation of Megamitochondria in the Rat Liver by Coenzyme Q10
Authors: Adachi Kayo , Matsuhashi Tatsuo , Nishizawa Yuji , Usukura Jiro , Popinigis Jerzy , Wakabayashi Takashi
Published: April 2009

The effects of coenzyme Q10 (CoQ10) on the hydrazine-induced changes in the structure of mitochondria and those in antioxidant systems of the liver were investigated using rats as experimental animals. Animals were placed on a powdered diet containing 1.0% hydrazine for 7-8 days in the presence or absence of the combined treatment with CoQ10. Results obtained were as follows: (a) treatment of animals with CoQ10 prevented the hydrazine-induced formation of megamitochondria in the liver; (b) changes observed in the liver of the hydrazine-treated animals in comparison to the control were increases in the contents of α-tocopherol and CoQ analogs, increases in the levels of lipid peroxidation, decreases in the level of reduced glutathione with increases in that of oxidized glutathione, and increases in the ratio of unsaturated to saturated fatty acids in phospholipid domains of mitochondrial membranes; and (c) administration of CoQ10 to hydrazine-treated animals suppressed enhanced lipid peroxidation and improved lowered adenosine diphosphate/O ratios of mitochondria. The present data suggest that CoQ10 suppresses the hydrazine-induced formation of megamitochondria by scavenging free radicals generated from hydrazine and its metabolites.
Dental Dysplasia in Rats and Mice
Authors: Losco Patricia E.
Published: April 2009

Malformations of the maxillary incisors, diagnosed as dental dysplasia, were observed as a spontaneous background lesion in 3% (females) to 9% (males) of CD-1® mice and 14.5% (females) to 10.5% (males) of CD@ (Sprague-Dawley) rats in a chronic inhalation study. Lesions were reported grossly as overgrown, maloccluded, or malformed incisors. Microscopic findings included tooth pulp and periodontal abscesses, fractured and necrotic teeth, periodontal cysts, malformations of the incisor roots, and expansile masses, including odontomas, of the incisor roots. Development of lesions followed a pattern of tooth pulp necrosis and/or traumatic disruption of the epithelial root sheath at the base of the tooth. Feeding a powdered ration, which reduced the normal wearing of the incisors, and repeated clipping of overgrown incisors were believed to contribute to the incidence of disease.
Study of the Population of Enterochromaffin-Like Cells in Mouse Gastric Mucosa after Long-Term Treatment with Ebrotidine
Authors: Romero Alfonso , Gómez Francisca , Villamayor Frederic , Sacristán Aurelio , Ortiz José-Alfonso
Published: April 2009

The possible hyperplastic effect on the mouse gastric mucosa following administration of 500 mg/kg of ebrotidine for 18 mo was investigated. The animals were taken from the study of carcinogenesis in mouse carried out with this product. Two different aspects were considered to assess such a possible hyperplastic effect. The height of the fundic and antral mucosa was microscopically measured in several points. Histologic sections obtained from standardized levels of the stomach were used. The density of argyrophil cells in the gastric mucosa has been also quantified, in order to identify enterochromaffin-like (ECL) cells, the most abundant among the cells that have this property. Grimelius' silver staining method was used to identify ECL cells. The cell count was performed under ×400 magnification, and the length of mucosa examined was determined by computer-assisted image analysis. This study complements the mouse carcinogenesis study, in which no differences in tumor incidence were found between treated and control animals. The results show that administration of 500 mg/kg/day of ebrotidine for 18 mo to mice did not induce any hyperplastic effect on the gastric mucosa comprising its various cell types or any specific, diffuse, or focal hyperplasia of ECL cells.
Overexpression of Cytochrome P-450 Isoforms Involved in Aflatoxin B1 Bioactivation in Human Liver with Cirrhosis and Hepatitis
Authors: Kirby Gordon M. , Batist Gerald , Alpert Lesley , Lamoureux Esther , Cameron Ross G. , Alaoui-Jamali Moulay A.
Published: April 2009

Studies were carried out to test the hypothesis that inflammatory liver disease increases the expression of specific cytochrome P-450 isoenzymes involved in aflatoxin B1 (AFB) activation. The immunohistochemical expression and localization of various human cytochrome P-450 isoforms, including CYP2A6, CYP1A2, CYP3A4, and CYP2B1, were examined in normal human liver and liver with hepatitis and cirrhosis. The constitutive expression of CYP3A4 in normal liver showed a characteristic pattern of distribution in centrilobular hepatocytes, whereas CYP1A2, CYP2A6, and CYP2B1 1 were expressed uniformly throughout the liver acinus. In sections of liver infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), the expression of CYP2A6 was markedly increased in hepatocytes immediately adjacent to areas of fibrosis and inflammation. CYP3A4 and CYP2B 1 were induced to a lesser degree, and expression of CYP1A2 was unaffected. In HBV-infected liver, double immunostaining revealed that overexpression of CYP2A6 occurred in hepatocytes expressing the HBV core antigen. In HCV-infected liver, CYP2A6, CYP3A4, and CYP2B 1 were overexpressed in hepatocytes with hemosiderin pigmentation. These results suggest that alterations in phenotypic expression of specific P-450 isoenzymes in hepatocytes associated with hepatic inflammation and cirrhosis might increase susceptibility to AFB genotoxicity.
A Case Report of Superficial Necrolytic Dermatitis in a Beagle Dog with Diabetes Mellitus
Authors: Yoshida Midori , Barata Kyoko , Ando-Lu Jin , Takahashi Masakazu , Maekawa Akihiko
Published: April 2009

A case of superficial necrolytic dermatitis in a young laboratory beagle dog with diabetes mellitus was investigated. Macroscopically, the skin lesion was restricted to paws showing erosion and swelling of the interdigital areas. The most predominant histopathological feature was upper-epidermal vacuolation of keratinocytes. In the pancreas, the number and size of islets were found to be markedly reduced, and only glucagon-positive cells were detected. In the liver, severe and widespread vacuolation of hepatocytes was observed. Blood biochemical assays showed that the serum glucose and plasma glucagon levels were increased. In addition, levels of individual amino acids varied markedly, although the total amino acid concentration was within the normal range. From these results, it was suggested that the skin lesion in this case was primarily caused by hyperglucagonemia in diabetes mellitus.
Utilization of Electron Probe Microanalysis in Gadolinium-Treated Mice
Authors: Wasserman Arthur J. , Monticello Thomas M. , Feldman Robert S. , Gitlitz Peter H. , Durham Stephen K.
Published: April 2009

Gadolinium is used as a contrast media for magnetic resonance imaging and, experimentally, to block Kupffer cell phagocytosis. In this study, we utilize electron probe microanalysis to determine the subcellular localization of gadolinium chloride (GdCl 3) administered to mice in a short-term toxicology study. Male CD-1 mice were administered 0.0, 2.5, or 8.0 mg/kg GdCl3 iv for 14 consecutive weekdays. Liver-associated enzymes were significantly elevated in high-dose animals only and correlated histologically with multifocal, hepatocellular degeneration associated with a neutrophilic infiltrate. Morphological investigations were performed on high-dose animals. Hepatocytes and Kupffer cells had morphologic features of cellular injury consisting of swollen mitochondria and vesiculated profiles of endoplasmic reticulum. Hepatocytes, Kupffer cells, bile canaliculi, and neutrophils in the liver contained discrete aggregates of electron-dense granular material, as did pulmonary interstitial macrophages, splenic macrophages, and mesangial cells of the renal glomerulus. The intracellular granular material in the liver, lung, spleen, and kidney was confirmed as gadolinium by qualitative electron probe microanalysis. These results document both hepatic and extra-hepatic accumulation of gadolinium in cells of the mononuclear phagocytic system and highlight the importance of electron probe microanalysis in toxicologic assessment.
Spontaneous Lesions in Aging FVB/N Mice
Authors: Mahler Joel F. , Stokes William , Mann Peter C. , Takaoka Masaya , Maronpot Robert R.
Published: April 2009

The FVB/N mouse strain was created in the early 1970s and has since been used extensively in transgenic research because of its well-defined inbred background, superior reproductive performance, and prominent pronuclei of fertilized zygotes, which facilitate microinjection of DNA. Little is known, however, about the survivability and spontaneous disease of nontransgenic FVB/N mice. Therefore, the purpose of this study was to determine survival to 24 mo of age and the incidence of neoplastic and nonneoplastic disease at 14 and 24 mo of age. At 14 mo of age, the incidence of tumor-bearing mice was 13% in males (n = 45) and 26% in females (n = 98). All tumors in males and most in females at this time were alveolar-bronchiolar (AB) neoplasms of the lung. Survival to 24 mo of age was approximately 60% in both sexes (29/50 males, 71/116 females), and the incidence of mice with tumors at this time was 55% in males and 66% in females. In decreasing order of frequency, the following neoplasms were observed in >5% of subjects: in males, lung AB tumors, liver hepatocellular tumors, subcutis neural crest tumors, and Harderian gland adenomas; in females, lung AB tumors, pituitary gland adenomas, ovarian tumors (combined types), lymphomas, histiocytic sarcomas, Harderian gland adenomas, and pheochromocytomas. Compared with other mouse strains, the observed incidences of tumors in FVB/N mice suggest a higher than usual rate of lung tumors and a lower than usual incidence of liver tumors and lymphomas. This tumor profile should be considered in the interpretation of neoplastic phenotypes in FVB/N-derived transgenic lines.
Diet: The Neglected Variable in Chemical Safety Evaluations
Authors: Newberne Paul M. , Sotnikov Alexander V.
Published: April 2009

The objectives of this review are to alert the community of toxicologic pathologists to the types and significance of various diets fed to experimental animals used in safety evaluations of drugs and other chemicals, to acquaint investigators with dietary nutrients and contaminants of significance to research animals, to review some of the consequences of improper or inadequate diets on results of safety evaluations, and, finally, to offer a brief introduction to a highly promising new digital specimen technology for evaluating histopathology of tissues from animals used in safety evaluations with the aid of computers. Results that form the basis for this review have accumulated for more than 4 decades during research conducted during appointments at the University of Missouri, Columbia; Auburn University; Massachusetts Institute of Technology; and Boston University School of Medicine. The methods used in these studies have generally been state-of-the-art at the time the studies were conducted and involved an integration of techniques and methods used in fundamental nutrition, toxicology, and experimental pathology. Some of these investigations have shown that contaminants, naturally occurring and man-made, intentional and nonintentional, do occur in commercial animal diets; that essential nutrients, including total calories, protein, and fat, can be provided in less or more than adequate amounts for the species of animal used in safety evaluations; and that such variables can influence responses to chemicals through effects on xenobiotic metabolism, immunocompetence, secondary diseases, and other factors. Under such conditions, serious differences in final interpretation of human risk for a drug or other chemical can contribute to failure to gain approval for a potentially valuable therapeutic agent. This review discusses the significance of various dietary components with examples of their effects on response of the animal to chemicals and demonstrates why nutrients, new technologies for assessing their effects, and other components in the diet should be accorded greater consideration by investigators and regulators.
Relationship of Hydroquinone-Associated Rat Renal Tumors with Spontaneous Chronic Progressive Nephropathy
Authors: Hard Gordon C. , Whysner John , English J. Caroline , Zang Edith , Williams Gary M.
Published: April 2009

Hydroquinone exposure has been reported by the National Toxicology Program (NTP) to produce renal tubule adenomas and to exacerbate spontaneous chronic progressive nephropathy (CPN) in male F344 rats. A mechanism for hydroquinone-related tumorigenesis has not been established, but CPN is known to involve, and hydroquinone produces, enhanced renal tubule cell proliferation. Through an independent review of the renal histopathology from the NTP study, the grade of CPN and the presence of atypical tubule hyperplasia and adenomas was evaluated. Hydroquinone exposure in males at 50 mg/kg produced a statistically significant increase in the grade of CPN. At 0, 25, and 50 mg/kg, 0/44, 4/49, and 15/51 male rats had either atypical tubule hyperplasias or adenomas; all were within areas of severe or end-stage CPN and were statistically significantly associated with CPN grade. Additionally, there was a dose-related increase in profiles believed to represent new tubule proliferation within areas of advanced CPN, as well as an apparent expansion of these into unusual complex tubule profiles in end-stage kidneys of the high-dose male group. In summary, this histopathological review suggests a mechanism for hydroquinone-related adenoma formation that includes enhancement of the severity of CPN coupled with stimulation of tubule proliferation.
Comparison of Ultrastructural Changes in Thyrotrophs of the Rat Pituitary Between Intermittent and Continuous Treatments with Sulfadimethoxine
Authors: Shimo Takeo , Mitsumori Kunitoshi , Takahashi Masakazu , Katayama Junichi , Saito Akemi , Yoshida Hidenobu , Aoki Yasuji , Onodera Hiroshi , Takahashi Michihito
Published: April 2009

To clarify relationships between serum thyroid-stimulating hormone (TSH) levels and ultrastructural changes in thyrotrophs caused by intermittent or continuous treatments with antithyroid compound, male Fischer-344 rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN) were given water containing 0.1% sulfadimethoxine (SM) for 8 wk and then sacrificed (Group 1). Additional groups were examined 2 wk after withdrawal (Group 2), after 4 wk retreatment following a 2-wk withdrawal period (Group 3), and after 14 wk continuous exposure (Group 4). Control rats (Group 5) remained untreated for 8 wk after the DHPN initiation. Microscopic examination revealed hypertrophy of thyrotrophs and depletion of TSH-positive material in Groups 1, 3, and 4 but a return to normal in Group 2. Electron microscopic examination of thyrotrophs in the anterior pituitary in Groups 1, 3, and 4 revealed dilated rough endoplasmic reticulum (ER) cisternae with intracisternal dense granules as well as diminished numbers of intracytoplasmic secretory granules, these changes being most marked in Group 1 and least pronounced in Group 4. The number of intracytoplasmic secretory granules in Group 3 was much lower than in Group 4, as demonstrated by morphometric analysis. In Group 2, thyrotrophs showed dilated rough ER cisternae without intracisternal dense granules and essentially the same component of intracytoplasmic secretory granules as Group 5. The present study suggests that while prolonged continuous treatment with SM results in gradual acclimation to an increased demand for TSH, intermittent treatment elicits a persistent state of reduced TSH storage in thyrotrophs due to a continued strong feedback through the hypothalamus-pituitary-thyroid axis.
1,3,5-Trinitrobenzene-Induced Alpha-2u-Globulin Nephropathy
Authors: Kim Soochong , Qualls Charles W. , Reddy Gunda , Stair Eric L.
Published: April 2009

Male and female Fischer-344 (F-344) and male NCI-Black-Reiter (NBR) rats were dosed with 0, 35.5, or 71 mg 1,3,5-trinitrobenzene (TNB)/kg/day for 10 days. Male F-344 rats were dosed with TNB (0 and 35.5 mg/kg) for 20 and 30 days. Hematoxylin and eosin and Mallory-Heidenhain stains and alpha-2u-globulin and proliferating cell nuclear antigen immunohistochemical stains were performed on kidney sections. All treated male F-344 rats exhibited dose-related accumulation of hyaline droplets containing alpha-2u-globulin in proximal tubules. The kidney weights were significantly increased in male and female rats treated with TNB. Significant increases in cell proliferation in proximal tubules were observed in male F-344 rats. Renal changes observed in TNB-treated rats appeared identical to those from other chemicals that induce alpha-2u-globulin nephropathy in male rats. No hyaline droplet accumulation was found in female F-344 and male NBR rats at any doses. We can conclude that TNB induces dose-related exacerbation of hyaline droplets containing alpha-2u-globulin in male rat kidney and subsequent cell proliferation.
Hypertrophy and Prolonged DNA Synthesis in Smooth Muscle Cells Characterize Pulmonary Arterial Wall Thickening After Monocrotaline Pyrrole Administration to Rats
Authors: Lappin Patrick B. , Roth Robert A.
Published: April 2009

Monocrotaline pyrrole (MCTP) is a highly reactive pneumotoxic metabolite of the pyrrolizidine alkaloid plant toxin monocrotaline. When administered to rats, it causes a delayed and progressive lung injury, vascular remodeling, and pulmonary hypertension. Structural remodeling consists of endothelial cell swelling followed by increased thickness of the vascular media in small pulmonary arteries and muscularization of normally nonmuscular arteries. Experiments were performed to characterize DNA synthesis and cell proliferation in vascular smooth muscle cells (VSMCs) after MCTP and to determine their relationship to changes in the thickness of the arterial medial layer of pulmonary resistance vessels. Male Sprague-Dawley rats were treated with MCTP (3.5 mg/kg, intravenously) or its vehicle (dimethylformamide). To label cells actively synthesizing DNA, rats were given the thymidine analog, bromodeoxyuridine (BrdU), 3 times by intraperitoneal injection during the 24 hr preceding euthanasia. Using immunohistochemistry, BrdU incorporation was quantified as a ratio of labeled nuclei to total nuclei. Within 5 days after MCTP administration, the thickness of the medial smooth muscle layer in arteries 60-250 μm in diameter was increased, prior to evidence of right heart hypertrophy. BrdU incorporation by VSMCs in pulmonary arteries was not different in vehicle- and MCTP-treated rats for the first 48 hr after treatment. However, MCTP caused a significant increase in DNA synthesis in VSMC on days 3-8 in arteries up to 250 μm in diameter. Although increased DNA synthesis precedes cell proliferation, the relative number of medial VSMCs did not increase over 8 days, suggesting that hypertrophy alone was responsible for the increased thickness of the arterial media. These results demonstrate that MCTP causes thickening of the media of pulmonary vessels through VSMC hypertrophy and that the prolonged DNA synthesis that accompanies VSMC hypertrophy is not followed by proliferation.
Review Article: A Medium-Term Rat Liver Bioassay as a Rapid In Vivo Test for Carcinogenic Potential: A Historical Review of Model Development and Summary of Results from 291 Tests
Authors: Shirai Tomoyuki
Published: April 2009

A bioassay system for rapid detection of carcinogenic agents has been developed using male Fischer 344 rats to bridge the gap between long-term carcinogenicity tests and short-term screening assays. The system, called the medium-term liver bioassay, is fundamentally based on the 2-stage hypothesis of tumor production, employing initiation by diethylnitrosamine (200 mg/kg, ip) in the first stage and test chemical administration during the second, in combination with two-thirds partial hepatectomy. It requires only 8 wk for animal experimentation and a further few weeks for quantitative analysis of immunohistochemically demonstrated glutathione S-transferase placental form positive hepatic foci. A total of 291 chemicals/substances have already been analyzed in our laboratory. Among 63 chemicals that were proved to be carcinogenic in the liver of rat and/or mouse, 57 (90%) gave positive results irrespective of their mutagenicity. Negative compounds include peroxisome proliferators and tamoxifen. Even nonhepatocarcinogens were positive at a rate of 24%. Eighty-six percent (12/14) of mouse liver carcinogens were also positive. On the other hand, only 2 out of 45 noncarcinogens showed very weak positivity. Thus, the efficacy of the system for hepatocarcinogens has been well established. This bioassay is increasingly regarded as an appropriate alternative test for carcinogenicity risk assessment and is practically used for a rapid evaluation of hepatocarcinogenicity of chemicals.
A PCR-RFLP Method for the Detection of Helicobacter hepaticus in Frozen or Fixed Liver from B6C3F1 Mice
Authors: Malarkey David E. , Ton Thai-Vu , Hailey James R. , Devereux Theodora R.
Published: April 2009

Establishing the diagnosis of Helicobacter hepaticus infection in mouse liver has recently become important for the interpretation of rodent carcinogenicity bioassays. A seminested primer polymerase chain reaction (PCR) amplification of the bacterial 16S ribosomal RNA gene in combination with a restriction fragment length polymorphism (RFLP) assay was designed to identify and distinguish H. hepaticus from H. muridarum and H. bilis in mouse liver. The PCR-RFLP assay was applied to formalin-fixed, paraffin-embedded and, when available, corresponding frozen liver tissues from male and female B6C3F, mice with or without histologic evidence of infection from various National Toxicology Program 2-yr bioassay studies. PCR products consistent with H. hepaticus were detected in 10-80% of livers from mice in studies with other evidence of infection that were frozen or fixed for less than 24 hr but not in liver fixed for several weeks. The sensitivity of the PCR-RFLP assay for H. hepaticus on formalin-fixed, paraffin-embedded mouse liver varied between studies from markedly decreased when compared to the results from frozen liver or histologic evaluation to nearly equivalent or more sensitive than histologic evaluation. The PCR-RFLP results appeared dependent on the duration of fixation and bacterial load but not on the presence of hepatitis, sampling from neoplastic or nonneoplastic liver, or sex of the mouse.
Histogenetic Stereological Reconstruction of Rat Basophilic, Clear, and Oncocytic Neoplastic Renal Cell Lesions Using Carbonic Anhydrase Type II-PAS Double-Stained Sections
Authors: Tsuda Hiroyuki , Iwase Teruhiko , Matsumoto Kazuyuki , Ito Mitsuya , Hirono Iwao , Nishida Yoshihisa , Takasuka Nobuo , Iwahori Yoshio , Ota Tomonori , Dae Joong Kim  , Kadenbach Bernhard
Published: April 2009

The histogenesis of 3 types of rat renal cell tumors (basophilic cell, clear cell, and oncocytic) was stereologically analyzed, with particular attention paid to transitions from normal tubules. Early nitrosamine-induced preneoplastic lesions, including dysplastic tubules (altered tubules), epithelial hyperplasias, and small adenomas, were reconstructed using serially sectioned specimens processed for carbonic anhydrase type II (CA) and periodic acid-Schiff (PAS) (CA-PAS) double staining to allow easier distinction of the nephron segments: Proximal tubules had a PAS-positive brush border and were weakly positive for CA in the cytoplasm; distal tubules were PAS negative and weakly positive for CA; collecting ducts were PAS negative and strongly positive for CA. Similarly, cytochrome c oxidase (CytOx) and CytOx-PAS double staining was also applied to confirm the character of oncocytic lesions. All basophilic lesions (7 of 7) showed transition to proximal tubules. Clear cell lesions positive for CA, on the other hand, showed transition to distal tubules in 4 of 9 (44.4%) lesions and to collecting ducts in 4 of 9 (44.4%) lesions, but in only 1 of 9 (11%) to a proximal tubule. All oncocytic lesions (16 of 16), characterized by positivity for both CA and CytOx, showed transition to collecting ducts. The results indicate that the origins of renal cell neoplasia are proximal tubules for the basophilic cell lesions, either proximal or distal tubules for their clear cell counterparts, and collecting ducts for oncocytic lesions.
Bad Apples: Paradigm Overhaul and the CNN/Time “Tailwind” Story
Authors: Cecil Matthew
Published: April 2009

By examining the responses of journalists to the CNN/Time “Tailwind” story of 1998, this article suggests that discourse-extensive repair work, termed paradigm overhaul, occurs on news analysis broadcasts. Paradigm overhaul may be viewed as a particular type of paradigm repair work in which the logic of journalism is reasserted in response to an outside challenge. Paradigm overhaul is central to broadcasts such as CNN's Reliable Sources and FOX's Fox News Watch, on which journalists criticize challenges to the objective news paradigm and in the process overhaul that paradigm, reasserting objective news without altering or even questioning its underlying assumptions. The article further suggests that paradigm overhaul may be viewed as a ritual activity, providing mark-ers that define the boundaries of a journalistic interpretive community, an activity that masks societal and institutional constraints from news workers.
HIV dementia: the role of the basal ganglia and dopaminergic systems
Authors: Berger Joseph R. , Arendt Gabriele
Published: April 2009

The clinical features of human immunodefiency virus (HIV) dementia exhibit the hallmarks of a subcortical dementia. These features include psychomotor slowing, apathy, bradykinesia and altered posture and gait similar to those observed in advanced Parkinson's disease. The dementia has the hallmarks attributed to subcortical dementia. The exquisite sensitivity of many of these patients to dopamine receptor blockade suggested a profound and, perhaps, selective abnormality of striatal dopaminergic systems. Additional investigations, electrophysiological, pathological, virological, metabolic and radiological studies, indicate that the basal ganglia are a major target of HIV infection. In this review, we describe the evidence for involvement of basal ganglia and, in particular, the dopaminergic systems, in HIV dementia. We also suggest novel therapeutic strategies that may be beneficial in the treatment of this disorder.
Does ‘rebound mania’ occur after stopping carbamazepine? A pilot study
Authors: Macritchie Karine A. N. , Hunt Neil J.
Published: April 2009

Withdrawal of lithium prophylaxis in patients with bipolar affective disorder has been shown to precipitate ‘rebound mania’, an effect which may negate its benefits in the poorly compliant. No studies have looked for similar effects on withdrawal of carbamazepine, an alternative and adjunctive prophylactic treatment. This retrospective study examined the effects of withdrawal of carbamazepine prophylaxis in patients with bipolar disorder. A systematic search for patients with bipolar disorder who stopped carbamazepine therapy whilst in remission was conducted, followed by case note review and interview. In a case series of six patients who stopped carbamazepine, four remained well for at least 3 months, one developed an episode of moderate depression and one remained well before resuming treatment after 1 month. None required admission or suffered a manic episode in the 3 months following cessation. This study does not support the existence of a carbamazepine ‘rebounD’ effect. It raises the possibility that recurrence after stopping carbamazepine may be less severe than the ‘rebound mania’ seen on lithium withdrawal. If this is the case, it may be a better choice of mood stabilizer in the poorly compliant. To date, there is insufficient evidence on which to base this choice. There is a need to examine this issue further through larger prospective and experimental studies on the effects of anticonvulsant withdrawal.