bluuebunny/crossref_metadata_2025 huggingface dataset:
Early Histopathologic and Ultrastructural Changes in the Heart of Sprague-Dawley Rats Following Administration of Soman
Authors: Tryphonas Leander , Veinot John P. , Clement John G.
Published: April 2009

Male Sprague-Dawley rats were given atropine methylnitrate (20 mg/kg) and HI-6 (125 mg/kg) ip 10 min before a single injection of 130 μg soman/kg sc, and the heart was examined by light and electron microscopy 10, 25, 45, 90, and 180 min after the onset of seizures. Seizures appeared within 6-11 min after treatment. Control rats were given saline sc in place of soman. Early myocardial lesions consisting of hypercontraction and hyperextension of sarcomeres, focal myocytolysis, and contraction bands were detected in individual or groups of myocardial fibers. Hypercontraction was characterized by shortening of the sarcomere length, disappearance of the I and H bands, and thickening of the Z line. In contrast, hyperextended sarcomeres had thickened I and H bands. Myocytolysis was characterized by a progressively severe focal dissolution of myofilaments and edema of the affected sarcoplasmic area. Contraction bands appeared to result from the breakdown of markedly hypercontracted myofibril bundles. Due to the presence of a number of surviving myofilaments and the preservation of the sarcolemmal tube, distortion of the overall myocytic structure was minimal. Changes in the mitochondria and other intracellular organelles were also minimal and nonspecific. The close resemblance of morphologic findings to those induced by catecholamines supports the view that soman-induced myocardial damage is secondary to a treatment-related release of unphysiologic amounts of endogenous catecholamines.
Proliferative Bone Lesions in Rats Fed a Diet Containing Glucocorticoid for up to Two Years
Authors: Zwicker Gary M. , Eyster Randy C.
Published: April 2009

A glucocorticoid was fed in the diet to 50 Sprague-Dawley rats/sex at 0, 0.03, 0.06, 0.12, 0.25, 0.50, and 1.0 mg/kg/day for up to 2 yr. A total of 1,400 rats were examined. Bone neoplasms (5 osteosarcomas and 2 osteomas), involving the head, occurred in 7 males that were fed the test compound at the highest dose (0.25 mg/kg) with long-term survivors. One osteoma and 1 hyperostotic lesion were seen in 2 males receiving lower doses (0.06 mg/kg and 0.12 mg/kg, respectively); 1 female rat that received the highest dose (1 mg/kg) had an osteosarcoma. The results suggest, but do not confirm, a relationship between glucocorticoid exposure and bone proliferations in male Sprague-Dawley rats. Other proliferative bone lesions included hyperostosis in a 0.12-mg/kg male, osteoma in a 0.06-mg/kg male, and osteosarcoma in 1 female at 1.0 mg/kg. The purpose of this report is to characterize the incidence and morphology of primary bone proliferative lesions found in rats of 1-yr glucocorticoid toxicity and 2-yr carcinogenicity studies conducted in our laboratory.
Confocal Laser Scanning Microscopy of Oncogene Localization in Rainbow Trout Cell Lines Derived from Normal and Tumor Tissue*1
Authors: Carter Charleata A. , Ellington William W. , Van Beneden Rebecca J.
Published: April 2009

We examined the localization and expression of the nuclear oncoprotein c-myc and the cytoplasmic membrane-associated oncoprotein c-ras in rainbow trout cell lines derived from both normal and tumor tissue in order to question whether c-myc and ras oncoprotein immunostaining was increased in cells derived from tumors compared to cells derived from normal tissue. Cell lines examined were derived from normal rainbow trout gonadal cells (RTG-2), a rainbow trout hepatoma (RTH-149), and a rainbow trout mesothelioma (RTM). Protein products of c-ras and c-myc were visualized in these 3 cell lines by employing fluorescein-labeled anti-mouse pan-ras and c-myc antibodies. The RTG-2 cells were used in this study as normal, control cells, and they exhibited little pan-ras and c-myc staining. The RTH-149 cell line (a tumorigenic cell line) exhibited positive pan-ras staining in regions of the membrane and cell cytoplasm. Localization of c-myc staining to perinuclear regions was punctate in RTH-149 cells. RTM cells (also a tumorigenic cell line) displayed a ras staining localization similar to the pattern seen in RTH-149 cells. RTM cells exhibit a diffuse perinuclear staining and, thus, display a more ubiquitous localization of c-myc than RTH-149 cells. Northern blot analysis indicated that c-myc expression was highest in RTM cells, whereas RTG-2 cells and RTH-149 cells expressed similar lower levels of c-myc expression. We were unable to detect significant ras expression in any of the cell lines by Northern blot analysis. In summary, the cell line derived from normal tissue, the RTG-2 cells, displayed little ras and c-myc immunostaining, whereas the cell lines derived from tumorigenic tissue, RTH and RTM cells, displayed increased immunostaining for c-myc and ras proteins.
Long-Lasting Effect of Dexrazoxane Against Anthracycline Cardiotoxicity in Rats
Authors: Torre Paola Della , Podestà Arturo , Pinciroli Giovanni , Iatropoulos Michael J. , Mazué Guy
Published: April 2009

The long-lasting protective effect of dexrazoxane (ADR-529) against doxorubicin- and epirubicin-induced cardiotoxicity was evaluated in the multiple-dose 35-wk rat model. Groups of 36 male Sprague-Dawley rats were given ADR-529 30 min before administration of cardiotoxic doses of doxorubicin (1 mg/kg/wk) or epirubicin (1.13 mg/kg/wk). The compounds were intravenously injected once weekly for 7 consecutive wk at ADR-529: anthracycline ratios ranging from 5:1 to 20:1. These ratios covered the entire chemotherapeutic range in humans and allowed studying the chronic progressive cardiomyopathy in our rat model. Animals were observed for up to 35 wk to follow the time course of the well-characterized cardiomyopathy, which was evaluated through the well-established qualitative/quantitative morphological grading. It was clearly demonstrated in this rat model that ADR-529, at the ratios administered, provided ample cardioprotection for a duration of 35 wk, which corresponds to 25 yr of equivalent human time.
Light Microscopic Comparison of Surfactant-Induced Eye Irritation in Rabbits and Rats at Three Hours and Recovery/Day 35*1
Authors: Maurer James K. , Parker Ron D.
Published: April 2009

Limited information exists on the pathologic changes occurring with surfactant-induced ocular irritation in the context of accidental human exposures and animal tests used to assess for such irritation. The purpose of this study was to begin to characterize the pathologic changes that occur with surfactants in the context of standard animal tests and compare the response in rats to that in rabbits. Representative anionic, cationic, and nonionic surfactants causing slight to severe ocular irritation were directly applied to the corneas of rabbits and rats at a dose of 10 μl. Eyes and eyelids of each animal were macroscopically examined for signs of irritation beginning 3 hr after dosing and periodically until recovery or day 35. Eyes and eyelids from animals in each group were collected for microscopic examination after 3 hr and at recovery or day 35. Microscopically, all of the surfactants caused erosion, denudation, and/or necrosis of the conjunctival and corneal epithelium in rabbits and rats. Necrosis of keratocytes was observed in rabbits and rats treated with the severely irritating cationic surfactant and in rats treated with anionic surfactants that were mildly irritating and moderately irritating. Corneal endothelial changes were observed in rabbits and rats with only the cationic surfactant. Changes in eyes of rabbits and rats that had not recovered by day 35 included decreased prominence of goblet cells, conjunctivalization of the corneal epithelium, neovascularization and fibrosis of the cornea, and presence of devitalized stroma. Overall, the changes in rabbits and rats were similar and suggest that the rat may be used as a surrogate for the rabbit in studies to understand better mechanisms of surfactant-induced eye irritation.
Alterations in Glomerular Anionic Sites in the Autologous Phase of Canine Anti-Glomerular Basement Membrane Nephritis
Authors: Sugimoto Jiro , Wasaki Masahiko , Inoue Yoshimi , Shirota Kinji , Nomura Yasuo
Published: April 2009

There have been a few studies on canine nephrotoxic glomerulonephritis produced by anti-glomerular basement membrane serum (AGBM), but these reports have not focused on an alteration in the charge properties of glomerular basement membrane (GBM). In this study, rabbit AGBM or normal rabbit serum (NRS) was given intravenously (2 ml/kg body weight) to 16 male beagle dogs. An alteration of anionic sites (ASs) of GBM was studied quantitatively using polyethyleneimine as a cationic probe by electron microscopy at weeks 1, 2, 4, and 8 postinjection. In AGBM-treated dogs, severe or mild proteinuria continued until week 2. At weeks 4 and 8, there was no significant difference in the intensity of proteinuria between AGBM- and NRS-treated groups. Until week 2 postinjection, there were significantly fewer ASs of GBM in AGBM-treated dogs than in NRS-treated dogs. At week 8, however, there was no difference in ASs of GBM between AGBM- and NRS-treated dogs. The fact that a reduction of glomerular AS occurred in AGBM-treated dogs with severe or mild proteinuria and the recovery of AS in the GBM coincided with an improvement of proteinuria suggested that alteration of the glomerular ASs might play an important role in the pathogenesis of proteinuria in canine anti-GBM nephritis.
The Contribution of the Mouse in Hazard Identification Studies
Authors: Maronpot R.R. , Boorman G.A.
Published: April 2009

Because there is usually more extensive toxicity, metabolism, and pharmacokinetic information for pharmaceuticals as opposed to environmental agents, including pesticides, the argument has been made that carcinogenicity testing in two rodent species may not have been necessary for carcinogenicity testing of pharmaceuticals. On the basis of numerical data only, it may be argued that carcinogenicity testing of pharmaceuticals in one species, typically the rat, is sufficient to identify potential human carcinogens. The argument that testing in a second species, typically the mouse, is redundant overlooks the value added by the second species carcinogenicity study. Bioassay data from the second species allows balance and perspective in evaluating the observed effects, and this is especially critical when there is a marginal, questionable, or inconclusive response in one species. Utilization of two species for carcinogen identification is the principal means for identifying trans-species carcinogens—those mostly likely to be carcinogenic in humans. Given that neither rat nor mouse are ideal surrogates for humans, concordant data from both species strengthens the ability to extrapolate findings to humans. We believe that testing in two species should continue to be the default approach used for carcinogen hazard identification whenever scientifically indicated until such time that acceptable and suitable alternatives are available. To utilize only one species for this important means of protecting human health is premature at this time.
Safety Assessment of Pharmaceuticals: Examples of Inadequate Assessments and a Mechanistic Approach to Assuring Adequate Assessment
Authors: Williams Gary M.
Published: April 2009

For a conventional organic new chemical entity (NCE) being developed as a pharmaceutical, standard regulatory safety assessment studies are required. Early in development, an NCE should undergo a safety/benefit analysis to justify further development. This analysis is made easier and more effective when comprehensive nonclinical data are available. One of the most important aspects of nonclinical toxicologic studies is to provide information on absence of potential carcinogenicity in humans. To avoid human exposures to potentially carcinogenic agents, even in early development of an NCE, the Decision Point Approach to carcinogen testing provides a useful guide to acquisition of mechanistically relevant data for risk assessment.
Cationic Amphiphilic Drug-Induced Phospholipidosis
Authors: Halliwell William H.
Published: April 2009

Phospholipidosis, a phospholipid storage disorder, defines an excessive accumulation of intracellular phospholipids. Phospholipids are structural components of mammalian cytoskeleton and cell membranes. The metabolism of this essential cell component is regulated by the individual cell and may be altered by drugs that interact with phospholipids or the enzymes that affect their metabolism. Xenobiotics or their metabolites that induce phospholipidosis include a wide variety of pharmacologic agents, including antibacterials, antipsychotics, antidepressants, antiarrhythmics, antianginals, antimalarials, anorexic agents, cholesterol-lowering agents, and others. Each of these drugs shares several common physiochemical properties: hydrophobic ring structure on the molecule and a hydrophilic side chain with a charged cationic amine group, hence the class term cationic amphiphilic drugs (CADs). This paper reviews the phospholipid metabolism, physiochemical characteristics of CADs, specificity of phospholipidosis in animals and humans, functional effects of phospholipidosis, interaction of CADs with biologic membranes and lysosome metabolism, influence of CADs on phospholipases and phospholipid synthesis, and a proposed mechanism for induction of phospholipidosis in the lung. In human risk assessment, investigators should consider the many factors in evaluating a drug that induces phospholipidosis in animals. These include: the therapeutic class of drug, presence of active metabolites, tissue or organ selectivity in animals and humans, influence of concurrently administered drugs, reversibility of effect, and other factors that increase or decrease the induction of phospholipidosis. Generalities regarding the etiology, incidence, and effect of the drug on a specific host may not be made. Each drug must be evaluated separately to identify the risk when administered for therapeutic effect in humans.
Environmental Protection Agency Risk Assessment— Process and Toxicologic Pathology
Authors: Copley Marion P.
Published: April 2009

Risk assessment of a pesticide includes the identification of hazard, dose-response, exposure assessment, and risk characterization. Toxicology study reports undergo several levels of scientific and regulatory review in the Environmental Protection Agency's (EPA's) Office of Pesticide Programs. A Health Effects Division (HED) scientist reviews the reports. The resulting Data Evaluation Records are presented to several internal HED Peer Review committees to ensure consistency across chemicals in establishing which hazard end points to use when determining the reference dose and carcinogenicity potential for use in dietary and nondietary risk assessments. There may also be external reviews. The toxicologic pathologist can impact many steps in this process. The noncancer end points are just as important as the cancer end points when evaluating the hazard component of a pesticide. The toxicologic pathologist can assist in the hazard and risk characterization by being clear and concise, carefully defining terms and relating individual lesions to the animal, study, and database as a whole. The preceding will assist the HED in fulfilling EPA Administrator Carol Browner's guidance for risk characterizations that are transparent, clear, concise, and reasonable.
Morphological and Ultrastructural Study of the Histogenesis of Meningeal Granular Cell Tumors in Rats
Authors: Yoshida Toshinori , Mitsumori Kunitoshi , Harada Takanori , Maita Keizo
Published: April 2009

To clarify the cell of origin of granular cell tumors in the rat brain, light and/or electron microscopic examinations were performed on 40 cases of spontaneous meningeal tumors in Wistar (Jcl: Wistar) rats. The meningeal tumors were histologically subclassified into 3 types: meningothelial meningiomas (MMs), 3 cases; granular cell tumors (GCTs), 28 cases; and mixed forms (MIXs) of GCTs and MMs, 9 cases. Of these tumors, 2 MMs, 2 GCTs, and 3 MIXs were examined by transmission electron microscopy. Tumor cells of MMs were characterized by cytoplasmic intermediate filaments and prominent interdigitating cell processes often connected with cellular junctions without surrounding basal laminae. GCTs were composed of 2 cell types: granular cells with many dense bodies and filamentous cells with fine intermediate filaments. MIXs consisted of granular cells, filamentous cells, and intermediate cells. The tumor cells in GCTs and MIXs were apposed to each other and connected with cellular junctions. MIXs displayed a spectrum of cellular differentiation in that 2 MIXs had a close morphological resemblance to GCTs and the other one to MMs. These findings indicate there might be a histogenetic sequence among MMs, GCTs, and MIXs. The present study supports the suggestion that GCTs and MIXs may be variants of MMs from the meningeal arachnoid cell.
Mixed Mesenchymal Tumor in the Kidney of a Young Beagle Dog
Authors: Robison Rodney L. , Grosenstein Paul A. , Argentieri Gregory J.
Published: April 2009

A rare spontaneous tumor was detected in the kidney of an 11-mo-old beagle dog. The tumor was a well-circumscribed cortical mass and was composed of a heterogeneous population of connective tissue cell types. While the primary cell type was a spindle cell associated with prominent collagen deposition, other areas contained bands of smooth muscle cells and poorly cellular myxomatous tissue. The presence of smooth muscle cells was confirmed by transmission electron microscopy and immunoperoxidase techniques. Based on the results, the tumor was diagnosed as a benign mixed mesenchymal tumor.
Rhamnus cathartica (Buckthorn) Hepatocellular Toxicity in Mice
Authors: Lichtensteiger Carol A. , Johnston Nancy A. , Beasley Val R.
Published: April 2009

The toxicity of the plant Rhamnus cathartica was assessed in mice after the plant was identified as a potential cause of an idiopathic neurologic disease in horses. Another member of the Rhamnaceae family, Karwinskia humboldtiana, is neurotoxic to mammals and birds and can induce hepatic degeneration and necrosis. To investigate the toxicity of R. cathartica, a 34-day feeding trial in mice was conducted using a complete rodent diet with 0, 5, or 25% added R. cathartica. No clinical signs or gross lesions were seen, and all major tissues were histologically normal except the liver. The livers of mice fed R. cathartica had marked hepatocellular swelling. Results from periodic acid-Schiff reaction staining and from electron microscopy confirmed that the swelling was due to deposits of monoparticulate glycogen (β particles) in the cytoplasm. Glycogen deposition is an uncommon toxic change in cells. Apparently, compound(s) in R. cathartica directly or indirectly interfered with glycogen metabolism (either glycogenesis or glycogenolysis). Mechanistic and chronicity studies with R. cathartica are needed to investigate the pathophysiology of the glycogen disturbance and to determine if hepatic injury progresses and if other organs will be injured.
Carbon Tetrachloride-Induced Hepatotoxicity Enhances the Development of Pulmonary Foam Cells in Rats Fed a Cholesterol-Cholic Acid Diet
Authors: Shibuya Kazumoto , Tajima Masanori , Yamate Jyoji , Saitoh Toshiki , Nunoya Tetsuo
Published: April 2009

The effect of CCl 4-hepatotoxicity on the development of pulmonary foam cells (PFCs) was studied using 4 groups of rats. Rats in the control group were fed a standard diet; rats in the second group were fed a hyper β-lipoproteinemic (HB) diet consisting of the standard diet, 4% cholesterol, and 1% cholic acid; rats in the third group were fed the standard diet and administered with CCl4 (1.0 ml/kg, ip, fortnightly) (CT); and rats in the fourth group were fed the HB diet and administered with CCl4 (HT). At feeding week 10, rats in the HB and HT groups developed hyper β-lipoproteinemia. The ratios of foamy, lipid-ingested monocytes (FMs) to blood monocytes (BMs) and the histologic scores of PFC development were significantly greater in the HB and HT groups than in the control and CT groups, respectively. The ratio of PFCs to alveolar macrophages from bronchopulmonary lavage fluid was significantly higher in the HT group than in the CT group. At feeding week 20, rats in the CT and HT groups suffered hepatic injury and hypo β-lipoproteinemia. Despite hypo β-lipoproteinemia, the FM and PFC development, the ratio of BMs in differential leukocyte counts, and latex-phagocytotic activity of BMs were enhanced in the HT group. Furthermore, markedly enlarged FMs, described here as giant-FMs, that contained numerous lipid droplets in their abundant cytoplasm appeared in the peripheral blood from rats in the HT group. Histologically, embolism caused by giant-FMs in the pulmonary blood vessels and intraalveolar accumulation of PFCs were detected with a high incidence in the HT group. The present study suggests that CCl4-hepatotoxicity may affect lipoprotein synthesis in the liver of hyper β-lipoproteinemic rats and defective or modified lipoproteins can be phagocytosed actively by BMs, and then BMs transform into FMs or giant-FMs, resulting in the PFC development and pulmonary embolism by giant-FMs.
Bleomycin-Induced Arthritis and Dermatitis in Rats
Authors: Kato Michiyuki , Takada Sanae , Ish Yoshikazu
Published: April 2009

We investigated the effect of the antitumor drug bleomycin (BLM) on synovial membrane and periarticular deep dermis in 10-wk-old young adult rats. BLM was found to induce edema, mononuclear cell infiltration and necrosis of the synovial membrane in the knee and tarsal joint, and inflammation in the deep dermis of the plantar hindfoot and digital pulvini in these rats after subcutaneous administration of 20 mg/kg for 3 days. After a 4-wk recovery period, foci of degenerative collagen bundles were observed in the deep dermis of the plantar hindfoot in spite of complete recovery of the lesions in the other dermal and synovial membrane sites. The synovitis was determined to begin with vesiculation of the macrophage-type lining cells, followed by edema and cell infiltration, especially near ligament insertion sites in the knee joint. The early dermal lesion consisted of dissociation of endothelial and subendothelial cells in small blood vessels thought to be postcapillary venules, edema, and monocyte infiltration. The severity of arthritis was greater in young adults than juvenile rats. From these results, BLM was shown to have a toxic effect on synovial lining cells and to induce inflammation in the synovial membrane and periarticular dermis.
Growth Factor Responses and Protooncogene Expression of Murine Mesothelial Cell Lines Derived from Asbestos-Induced Mesotheliomas
Authors: Goodglick Lee A. , Vaslet Charles A. , Messier Norma J. , Kane Agnes B.
Published: April 2009

Repeated intraperitoneal injections of crocidolite asbestos fibers induced diffuse malignant mesotheliomas in mice. A series of mesothelial cell lines was isolated from mice at different stages in the development of these tumors. The cell lines isolated from mice with mesotheliomas recapitulated their growth pattern in vivo and were tumorigenic when reinjected into syngeneic mice. Similar to human mesothelial cells, growth of the murine cell lines was stimulated by epidermal growth factor. Reactive mesothelial cells and mesotheliomas expressed the receptor for this growth factor. Crocidolite asbestos fibers have been reported to induce sustained expression of the c-fos and c-jun protooncogenes in rat pleural mesothelial cells in vitro (Heintz et al, Proc. Natl. Acad. Sci. USA 90: 3299-303, 1993). Human malignant mesotheliomas have been shown to express c-fos in situ (Ramael et al, Histol. Histopathol. 10: 639-643, 1995). Two of the cell lines derived from highly invasive murine mesotheliomas overexpressed c-fos and c-jun. This murine model recapitulates the histopathology, growth factor responses, and protooncogene expression of human malignant mesotheliomas.
Review Article: A Review of Experimental Methylmercury Toxicity in Rats: Neuropathology and Evidence for Apoptosis
Authors: Nagashima Kazuo
Published: April 2009

As an animal model for examining the pathogenicity of human organic mercury intoxication, rats have been used for the reproduction of human neurologic diseases. Rats experimentally exposed to methylmercury chloride showed clinical signs of neurologic dysfunction characterized by ataxic behavior. Neuropathology of the diseased animals consisted of lesions such as: (a) degeneration of the peripheral nerve and sensory root nerve with preservation of the motor root nerve; (b) degeneration of the posterior funiculus of the spinal cord; and (c) degeneration of cerebellar granule cells with preservation of Purkinje cells. These findings suggest the human neuropathology of this toxicity. The degeneration was characterized by nerve fiber damage or neuronal cell death accompanied by astrocytic gliosis and activated macrophages or microglias. For the cerebellar granule cells, the mechanism of neuronal cell death was shown to be apoptosis. This fact was verified by histologic and ultrastructural findings as well as by in situ nick-end labeling and electrophoretic methods. Evidence of apoptosis involvement in cerebellar degeneration would provide a new viewpoint from which to analyze the selected degeneration of the nervous system in neurotoxicology.
A Uterine Choriocarcinoma in a Virgin Donryu Rat
Authors: Yoshida Midori , Shiraki Katsuhisa , Kudoh Kayoko , Ando-Lu Jin , Takahashi Masakazu , Maekawa Akihiko
Published: April 2009

A uterine choriocarcinoma was found in a 49-wk-old virgin Donryu rat given intrauterine administration of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) . The tumor was macroscopically present as a bloody cystic mass and microscopically composed of 2 kinds of cells: small basophilic cells similar to cytotrophoblasts in the rat placenta and large cells with big nuclei resembling giant trophoblasts. The giant cells were positive for 3β-hydroxysteroid dehydrogenase (3β-HSD), although immunohistochemical examination was negative or nonspecific for chorionic gonadotrophins, including β human chorionic gonadotrophin (βhCG), human placental lactogen (hPL), and placental glycoprotein (SP-1), or for placental alkaline phosphatase (ALP). However, the animal exhibited a slight mammotropic status. The results thus suggest a choriocarcinoma nature for this uterine tumor and that the tumor cells secrete a weakly mammotrophic hormone.
Time- and Dose-Dependent Development of Potassium Bromate-Induced Tumors in Male Fischer 344 Rats
Authors: Wolf Douglas C. , Crosby Lynn M. , George Michael H. , Kilburn Steve R. , Moore Tanya M. , Miller Richard T. , Deangelo Anthony B.
Published: April 2009

Potassium bromate (KBrO 3) is a rodent carcinogen and a nephro- and neurotoxicant in humans. KBrO3 is used in cosmetics and food products and is a by-product of water disinfection by ozonization. KBrO3 is carcinogenic in the rat kidney, thyroid, and mesothelium and is a renal carcinogen in the male mouse. The present study was designed to investigate the relationship of time and dose to bromate-induced tumors in male Fischer 344 (F344) rats and to provide some insight into the development of these tumors. KBrO 3 was dissolved in drinking water at nominal concentrations of 0, 0.02, 0.1, 0.2, and 0.4 g/L and administered to male F344 rats as the sole water source for 12, 26, 52, 78, or 100 wk. Renal cell tumors were present after 52 wk of treatment only in the high-dose group. Mesotheliomas developed after 52 wk of treatment on the tunica vaginalis. Mesotheliomas were present at sites other than the testicle after 78 wk of treatment, indicating that their origin was the testicular tunic. Thyroid follicular tumors were present as early as 26 wk in 1 rat each from the 0.1- and 0.2-g/L groups. The present study can be used as a basis for the determination of dose-time relationships of tumor development for a better understanding of KBrO3-induced cancer.
Use of DNA Repair-Deficient XPA Transgenic Mice in Short-Term Carcinogenicity Testing
Authors: Van Steeg Harry , Klein Hanneke , Beems Rudolf B. , Van Kreijl Coen F.
Published: April 2009

At present (putative) human carcinogens are identified via epidemiological studies and testing using the chronic 2-yr rodent bioassay. Both methods have severe limitations in that they are slow, insensitive, expensive, and are also hampered by many uncertainties. The development of methods to modify specific genes in the mammalian genome has provided promising new tools for use in identifying carcinogens and characterizing their (qualitative) risk. Several transgenic mouse lines are currently under study to test their possible use in short-term carcinogenicity testing. One such candidate alternative transgenic model is the XPA knock-out mouse. These mice have an almost complete deficiency in DNA nucleotide excision repair (NER). Nevertheless, XPA-deficient mice are viable and have a background of a low incidence of spontaneous development of cancers. Approximately 15% of the mice develop hepatocellular adenomas (only after 1.5 yr). After treatment with ultraviolet-B radiation or 7,12-dimethylbenz(a)anthracene, the XPA-deficient mice developed squamous cell carcinomas and papillomas, respectively, on their skin. Oral treatment of XPA-deficient mice with benzo[a]pyrene (B[a]P), 2-acetylaminofluorene (2-AAF), and 2-amino-l-methyl-6-phenylimidazo [4,5-b]-pyridine (PhIP) resulted in lymphomas (B[a]P), liver and bladder tumors (2-AAF), and intestinal adenomas plus lymphomas (PhIP). These results look encouraging, but it should be noted that the compounds and agents tested thus far have all been substrate for nucleotide excision repair. Animal studies with different genotoxic or nongenotoxic compounds, as organized for instance within the framework of the International Life Sciences Institute/Health and Environmental Sciences Institute program, are needed to further evaluate the suitability of the XPA model for short-term carcinogenicity testing.
Peripheral Neuroblastoma in a Young Beagle Dog
Authors: Matsushima Shuuichi , Maruyama Toshiyuki , Tor Mikinori
Published: April 2009

A peripheral neuroblastoma was found in the abdominal cavity of a young male beagle dog. The large tumor mass involved the left kidney and both adrenal glands. Histologically, a major portion of the neoplasm consisted of lobulated sheets of small round cells with hyperchromatic nuclei mixed with polygonal cells and neuropil. Small clusters of polygonal cells with abundant eosinophilic cytoplasm and a trabecular growth pattern were observed adjacent to some of the tumor lobules. Small, round neoplastic cells metastasized to lumbar lymph nodes and also to the adrenal glands. The neoplastic cells were positive for neuron-specific enolase, synaptophysin, and neurofilament protein. Electron micrographs revealed intracytoplasmic dense core granules, microtubules, intermediate filaments, and desmosomes in the cytoplasm of the neoplastic cells.
Tryptophan depletion impairs memory consolidation but improves focussed attention in healthy young volunteers
Authors: Schmitt Jeroen A. J. , Jorissen Brenda L. , Sobczak Sjacko , van Boxtel Martin P. J. , Hogervorst Eef , Deutz Nicolaas E. P. , Riedel Wim J.
Published: April 2009

Animal and human studies have provided evidence for serotonergic modulation of cognitive processes. However, the exact nature of this relationship is not clear. We used the acute tryptophan depletion (ATD) method to investigate the effects of lowered serotonin synthesis on cognitive functions in 17 healthy young volunteers. The study was conducted according to a placebo-controlled, double-blind, crossover design. Cognitive performance and mood were assessed at baseline and 5 and 9 h after administration of ATD. A specific impairment of word recognition, without effects on short-term memory, occurred during ATD. No memory deficits were seen if ATD was induced after acquisition of new words. The Stroop Test and dichotic listening task demonstrated a modality independent improvement of focussed attention after ATD. Fluency was also improved after ATD. ATD did not alter speed of information processing, divided attention or planning functions. These results indicate that serotonin is essential in the process of long-term memory consolidation, primarily in the first 30 min after acquisition. Improvement of specific cognitive processes by lowered 5-HT function may be linked to the removal of inhibitory actions of 5-HT in the cortex.
The effects of some antidepressant drugs on prepulse inhibition of the acoustic startle (eyeblink) response and the N1/P2 auditory evoked response in man
Authors: Phillips M. A. , Langley R. W. , Bradshaw C. M. , Szabadi E.
Published: April 2009

Both the acoustic startle (eyeblink) response and the N1/P2 complex of the auditory evoked potential can be suppressed by presentation of a brief low-intensity stimulus 30-500 ms before the ‘startle-eliciting’ stimulus (‘prepulse inhibition’, PPI). We examined the effects of three antidepressants on PPI of these two responses. Fifteen males (19-30 years) participated in four weekly sessions, in which they received placebo, amitriptyline (100 mg), fluvoxamine (100 mg), and reboxetine (4 mg) (p.o.), according to a balanced double-blind design. Twenty minute simultaneous recordings of electromyographic (EMG) responses of the orbicularis oculi muscle of the right eye and vertex auditory evoked potentials were carried out 195 min after drug ingestion. Sound stimuli (1 kHz) were presented in 40 trials separated by variable intervals (mean 25 s): (1) 40 ms, 115 dB (‘pulse alone’, 20 trials) and (2) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB (‘prepulse/pulse’, 20 trials). Under the placebo condition, both the EMG response and the N1/P2 complex showed >50% PPI. Fluvoxamine and reboxetine did not significantly alter the amplitude or PPI of either response. Amitriptyline significantly reduced the amplitudes of both responses; it had no effect on PPI of the EMG response, but significantly attenuated PPI of the N1/P2 complex. Amitriptyline also reduced arousal, as indicated by an increase in power of low-frequency electroencephalographic waves. The results confirm the susceptibility of the N1/P2 complex to PPI. The reduction of the amplitudes of the EMG response and N1/P2 complex by amitriptyline may be related to its sedative action. The differential effect of amitriptyline on PPI of the N1/P2 complex supports the suggestion that different mechanisms may be involved in PPI of this response and PPI of the N1/P2 complex.
The feline model of neuroAIDS: understanding the progression towards AIDS dementia
Authors: Podell Michael , March Philip A. , Buck Wayne R. , Mathes Lawrence E.
Published: April 2009

Feline immunodeficiency virus (FIV) is a neurotropic lentivirus that produces a protracted state of immunodeficiency and encephalopathy in the cat. Recent evidence has shown several similarities to the natural progression of human immunodeficiency virus infection (HIV-1) associated degenerative effects on the central and peripheral nervous systems. Similar to HIV-1, FIV-induced encephalopathy neurovirulence is strain dependent, results in progressive immunodeficiency and increasing early peripheral but not brain viral load, preferentially affects the developing nervous system, produces quantifiable behavioural and neurophysiological impairment that is not directly linked to neuronal infectivity, and induces neuronal injury and loss both in vivo and in vitro. This paper highlights the cumulative scientific body of evidence supporting the use of the feline model of neuroAIDS.
Manipulation of operant responding for an ethanol-paired conditioned stimulus in the rat by pharmacological alteration of the serotonergic system
Authors: Wilson A. W. , Costall B. , Neill J. C.
Published: April 2009

It is becoming increasingly clear that environmental stimuli play a critical role in the maintenance of drug taking behaviour. This has led to investigations into the neural mechanisms by which environmental stimuli can come to control behaviour using paradigms such as conditioned reinforcement. The majority of this work has involved the use of food-paired conditioned stimulus rodent paradigms. Relatively few studies have attempted to investigate the neuropharmacology of behaviour maintained by presentation of a stimulus paired with ethanol drinking. Several lines of research support an important role for brain serotonin (5-HT) neurotransmitter systems in the control of alcohol drinking behaviour. The aim of the present study was, initially, to establish a procedure in which rats respond for an ethanol-paired conditioned stimulus, and second, to study the effects of a range of serotonergic compounds previously shown to be effective in reducing oral ethanol self-administration, on responding for this conditioned stimulus. Results showed that the 5-HT releaser d-fenfluramine, the selective serotonin reuptake inhibitor fluoxetine, the 5-HT1A receptor agonist 8-hydroxy-2[di-n-propylamino]tetralin, the partial 5-HT1A receptor agonist buspirone, and the 5-HT1B/5-HT2C receptor agonist 1-(3-trifluoromethylphenyl)piperazine, but not the 5-HT2A/5-HT2C receptor agonist 1-(2, 5-dimethoxy-4-iodophenylaminopropane)-2, selectively reduced responding on a lever leading to presentation of an ethanol paired conditioned stimulus. In addition the non-specific D1/D2 dopamine receptor antagonist haloperidol was active in this paradigm. Results are consistent with involvement of the dopaminergic and 5-HT systems, in particular activation of 5-HT1A and 5-HT1B receptor subtypes, in mediation of the conditioned or secondary reinforcing properties of ethanol.
Sleep and daytime sleepiness the next day following single night-time dose of fluvoxamine, dothiepin and placebo in normal volunteers
Authors: Wilson S. J. , Bailey J. E. , Alford C. , Nutt D. J.
Published: April 2009

To explore the effects of sedating and non-sedating antidepressants, we conducted a placebo-controlled, double-blind cross-over study in 12 normal subjects of the effects of a single night-time dose of fluvoxamine 100 mg, dothiepin 100 mg or placebo on night-time sleep recorded at home, and sleepiness and performance the following day. Night-time sleep was altered significantly by both drugs, with main effects on rapid eye movement (REM) sleep and sleep continuity. Dothiepin increased total sleep time, REM latency and stage 2 sleep and decreased arousals, wake after sleep onset and stage 1, whereas fluvoxamine decreased total sleep time and REM time and increased wake after sleep onset. Sleep latencies in daytime naps were significantly shorter for dothiepin and longer for fluvoxamine, showing that subjects were more sleepy when taking dothiepin. Electroencephalograms (EEG) performed during performance tasks failed to distinguish significantly between drugs. There were no significant differences between groups on our measures of tracking performance or reaction time; however, these tasks were designed primarily to provide a standard setting in which to monitor continuous EEG, and were unsuitable to detect sleepiness effects themselves. Saccadic eye movement velocity, acceleration and deceleration showed small non-significant changes after both drugs. Mood self ratings showed no significant differences among the groups. Subjective measures of night-time sleep reflected the objective measures of sleep continuity, and the items for difficulty and speed of wakening in the morning were significantly higher (i.e. more difficulty and slower) in the dothiepin group. The home-recorded sleep findings after fluvoxamine in this study were very similar to sleep laboratory studies with other antidepressant drugs, thus providing more validation of the home recording method.
The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics?
Authors: Bantick R. A. , Deakin J. F. W. , Grasby P. M.
Published: April 2009

Increasing attention is being directed towards the role of the serotonergic system in the neurochemistry of schizophrenia and antipsychotic drug treatment. This review considers the 5-HT1A receptor in this context. In patients with schizophrenia, the majority of post-mortem studies have reported increases in 5-HT1A receptor density in the prefrontal cortex in the approximate range 15–80%. Although the pathophysiological significance of this finding is unclear, given the location of a major proportion of these receptors on pyramidal cells, it may reflect an abnormal glutamatergic network. In terms of drug treatment, 5-HT1A agonists clearly display anticataleptic activity in rats. In addition, 5-HT1A agonists consistently increase dopamine release in the prefrontal cortex in rodents, which is an effect that might be predicted to improve negative symptoms. 5-HT1A agonists augment classical neuroleptics in some rat models of antipsychotic action and may be capable of modulating the glutamatergic network therapeutically. Despite the encouraging preclinical data, there is a paucity of clinical studies of 5-HT1A agonist augmentation of neuroleptics in the treatment of schizophrenia. However, the clinical relevance may be clarified by the atypical antipsychotic drugs clozapine, quetiapine and ziprasidone which combine D2 receptor antagonism and 5-HT1A agonism. In conclusion, given the increased prefrontal 5-HT1A receptor density in the illness, and the anticataleptic activity of 5-HT1A agonists combined with their ability to evoke prefrontal dopamine release, there is now a sufficient rationale to examine thoroughly the role of the 5-HT1A receptor in schizophrenia and antipsychotic drug treatment.
Hypericum perforatum (St John's Wort): a non-selective reuptake inhibitor? A review of the recent advances in its pharmacology
Authors: Nathan Pradeep J.
Published: April 2009

Hypericum possesses a unique pharmacology in that it displays the pharmacology of many classes of antidepressants and new mechanisms not typical of standard antidepressants. The most potent of all its action is the moderate to high potency for inhibition of the reuptake of monoamines, serotonin, dopamine and noradrenaline and the amino-acid neurotransmitters GABA and glutamate. Unlike standard reuptake inhibitors, hypericum exerts this reuptake inhibition non-competitively by enhancing intracellular Na+ion concentrations. At a receptor level, chronic treatment with hypericum downregulates β1-adrenoceptor, upregulates post-synaptic 5-HT1Areceptors and 5-HT2receptors. Although the major constituent responsible for the antidepressant effect is thought to be hyperforin, other constituents such as hypericin, pseudohypericin, flavonoids and oligomeric procyanidines may also play a direct or indirect role. While reuptake inhibition may more than likely be responsible for most of the antidepressant effect, other mechanisms may also contribute alone or in combination to exert the overall antidepressant action.
Interactions between LY354740, a Group II metabotropic agonist and the GABAA-benzodiazepine receptor complex in the rat elevated plus-maze
Authors: Ferris P. , Seward E. , Dawson G. R.
Published: April 2009

Flumazenil, a benzodiazepine (BZ) receptor antagonist, and naloxone, a non-selective µ-receptor antagonist, were used to investigate whether the anxiolytic action of LY354740 [1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate], a Group II metabotropic glutamate receptor agonist, was mediated through the benzodiazepine binding site on the GABAA receptor and opioid pathways. LY354740 (1.0–10.0 mg/kg i.p.) induced dose-dependent anxiolytic-like effects in the rat elevated plus-maze. The anxiolytic-like effects of LY354740 (10.0 mg/kg) and the benzodiazepine receptor agonist, chlordiazepoxide (CDP, 5.0 mg/kg i.p.) were blocked by flumazenil (15.0 mg/kg i.p.). By contrast, naloxone (10.0 mg/kg i.p.) failed to affect the anxiolytic-like effects of either LY354740 or CDP. The behaviour of animals treated with flumazenil or naloxone alone did not significantly differ from that of animals treated with vehicle alone. This study suggests that the anxiolytic-like effects of LY354740 on the elevated plus-maze may be directly or indirectly mediated by the benzodiazepine binding site on the GABAA receptor complex.
The effects of flumazenil, Ro 15-4513 and β-CCM on the behaviour of control and stressed mice in the staircase test
Authors: Pokk Paavo , Väli Marika
Published: April 2009

The effects of flumazenil, Ro 15-4513 and β-CCM in the staircase test were studied in control and small platform (SP) stressed mice. SP stress was induced by placing mice on small platforms (3.5 cm in diameter) surrounded by water for 24 h. This model contains several factors of stress, such as rapid eye movement sleep deprivation, isolation, immobilization and falling into the water. The staircase test consisted of placing a mouse in an enclosed staircase with five steps and recording: (i) the number of rearings and (ii) steps made during 3 min. SP stress increased the exploratory activity of mice in the staircase test as demonstrated by an increase in the number of rearings and steps made. In control mice flumazenil (2.0 and 10.0 mg/kg), Ro 15-4513 (1.0 and 3.0 mg/kg) and β-CCM (1.0 and 2.0 mg/kg) exerted an anxiogenic effect that was demonstrated by an increase in the number of rearings without significant changes in the number of steps. Similar to control mice, flumazenil induced an anxiogenic effect in SP stressed mice as demonstrated by an increase in the number of rearings. However, the sedative effect of flumazenil as demonstrated by a decrease in the number of steps made was more pronounced in SP stressed mice. In the SP stressed mice, the anxiogenic effect of Ro 15-4513 and β-CCM was masked by their strong sedative effect and a decrease in both measures of exploratory activity (number of rearings and number of steps). These data suggest that SP stress induces hypersensitivity to the sedative effect of flumazenil, Ro 15-4513 and β-CCM in the staircase test.
Crossover trial of pagoclone and placebo in patients with DSM-IV panic disorder
Authors: Sandford J. J. , Forshall S. , Bell C. , Argyropoulos S. , Rich A. , D'Orlando K. J. , Gammans R. E. , Nutt D. J.
Published: April 2009

Pagoclone is a cyclopyrrolone that is believed to act as a partial agonist at the γ-aminobutyric acid (GABA) A/benzodiazepine (BDZ) receptor. In theory, such partial agonists should be anxiolytic but lack the adverse side-effects of sedation, tolerance and withdrawal associated with full GABA-A/BDZ agonists. The objective of the randomized double-blind crossover study was to assess whether pagoclone was an effective anti-panic agent and also to assess its side-effect profile. Patients recruited had a diagnosis of Panic Disorder (DSM-IV) with at least one panic attack per week. Following a 2-week screening period, patients entered a 6-week trial consisting of two 2-week treatment periods, each followed by a 1-week washout. Patients were randomly assigned to receive either pagoclone 0.1 mg t.d.s. or placebo on their first treatment period and the converse on their second. The primary measure was daily panic attack dairy. Fourteen patients completed the study, the mean number of panic attacks during screening was 5.8 ± 0.8 (SEM), this fell to 3.6 ± 0.5 during treatment with pagoclone (p = 0.05) and 4.3 ± 0.8 with placebo (p = 0.14). There was no significant difference on direct comparison of pagoclone with placebo or in any of the secondary measures (including Rickels withdrawal scale) or the adverse event profiles. The study provides preliminary evidence that pagoclone has anxiolytic properties in the absence of typical BDZ side-effects. This is consistent with its theoretical mode of action as a partial agonist at the GABAA/BDZ receptor.