bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Assessment
Authors: Brecher Ronald W.
Published: April 2009

Risk assessment, when applied to living systems, is the process of determining the types and likelihoods of adverse effects that may result from exposure to chemical, biological, or physical hazards. Risk assessment is used as a tool to help set regulations and guidelines to prevent or minimize adverse health effects of long-term exposures to low levels of toxicants. It is also applied to evaluating the safety of pharmaceuticals, to protecting workers exposed intermittently to hazardous materials in the workplace, and to evaluating the potential future consequences of past or current exposures. Most toxicological information used in human health risk assessment comes from in vivo experiments in animals and focuses on the pathological response occurring as a result of exposure to the toxicant. Dose and response data must then be extrapolated between individuals and species and from high to low doses, all of which increase the degree of uncertainty in risk estimates. This presentation provides a general overview of risk assessment, exploring its strengths, weaknesses, and ongoing evolution. The distinction between real and perceived risks is also discussed and is shown to be driven by the extent to which mechanistic information is available and how it is integrated into the risk assessment process. Finally, the presentation explores ways in which pathologists and risk assessors can work more closely to enhance risk assessment's ability to be a defensible tool for evaluating health concerns associated with chronic low-level exposures to toxicants in our environment.
The Pathways of Cell Death: Oncosis, Apoptosis, and Necrosis
Authors: Trump Benjamin E , Berezesky Irene K. , Chang Seung H. , Phelps Patricia C.
Published: April 2009

The pathways and identification of cell injury and cell death are of key importance to the practice of diagnostic and research toxicologic pathology. Following a lethal injury, cellular reactions are initially reversible. Currently, we recognize two patterns, oncosis and apoptosis. Oncosis, derived from the Greek word "swelling," is the common pattern of change in infarcts and in zonal killing following chemical toxicity, e.g., centrilobular hepatic necrosis after CC14 toxicity. In this common reaction, the earliest changes involve cytoplasmic blebbing, dilatation of the endoplasmic reticulum (ER), swelling of the cytosol, normal or condensed mitochondria, and chromatin clumping in the nucleus. In apoptosis, the early changes involve cell shrinkage, cytosolic shrinkage, more marked chromatin clumping, cytoplasmic blebbing, swollen ER on occasion, and mitochondria that are normal or condensed. Following cell death, both types undergo postmortem changes collectively termed "necrosis." In the case of oncosis, this typically involves broad zones of cells while, in the case of apoptosis, the cells and/or the fragments are often phagocytized prior to their death by adjacent macrophages or parenchymal cells. In either case, the changes converge to a pattern that involves mitochondrial swelling, mitochondrial flocculent densities and/or calcification, karyolysis, and disruption of plasmalemmal continuity. The biochemical mechanisms of cell death are currently under intense study, particularly concerning the genes involved in the process. Pro-death genes include p53, the ced-3/ICE proteases, and the Bax family. Anti-death genes include ced-9/Bcl-2 and the adenovirus protein E1B. It is clear that ion deregulation, particularly that of [Ca 2+]1 plays an important role in cell death following either apoptosis or oncosis. Genetic evidence strongly indicates that activation of proteases is an important step, possibly very near to the point where cell death occurs.
Effects of Dichlobenil on Ultrastructural Morphology and Cell Replication in the Mouse Olfactory Mucosa
Authors: Mancuso Mariateresa , Giovanetti Anna , Brittebo Eva B
Published: April 2009

The herbicide dichlobenil (2,6-dichlorobenzonitrile) is a tissue-specific toxicant inducing necrosis in the olfactory mucosa. Transmission electron microscopy showed vacuolations (1 hr) and necrosis (4 hr) in the Bowman's glands following intraperitoneal injection of dichlobenil (25 mg/kg) in C57B1 mice, whereas no lesions were noted in the olfactory neuroepithelium at these timepoints. Twenty-four hr following injection (25 mg/kg), most of the lamina propria and the olfactory epithelium were severely damaged; the basal lamina, nerves, and blood vessels in the lamina propria, however, remained intact. Following a lower dose (12 mg/kg), the lesions were not as pronounced. The effects of dichlobenil (6, 12, and 25 mg/kg) on cell replication in the olfactory mucosa, as determined by incorporation of 3H-thymidine 3 days later, were more pronounced in the lamina propria than in the neuroepithelium and occurred at a lower dose in the lamina propria than in the neuroepithelium. Together these studies support the previous proposal that dichlobenil induces a primary damage in the Bowman's glands.
Gadolinium Chloride Toxicity in the Rat
Authors: Spencer Andrew J. , Wilson Susan A. , Batchelor John , Reid Alexandra , Pees Jeremy , Harpur Ernest
Published: April 2009

Groups of 10 male and 10 female Sprague-Dawley rats were given a single intravenous injection of gadolinium chloride solution at dosages of 0 (saline vehicle), 0.07, 0.14, and 0.35 mmol/kg. Apart from 1 top-dose female, which died during dosing, 5 rats/sex/ group were necropsied 48 hr postdose, and the remaining 5 rats/sex/group were necropsied 14 days postdose. Macroscopic, hematological, and clinical chemistry analyses were undertaken on all animals that were necropsied. Histopathological examination was undertaken on all organs from high-dose and control animals necropsied 48 hr postdose and on tissues that showed treatment-related changes from all other rats necropsied either 48 hr or 14 days postdose. Major lesions related to gadolinium chloride administration consisted of mineral deposition in capillary beds (particularly lung and kidney), phagocytosis of mineral by the mononuclear phagocytic system, hepatocellular and splenic necrosis followed by dystrophic mineralization, mineralization of the fundic glandular mucosa in the absence of necrosis followed by mucous cell hyperplasia, decreased platelet numbers and increased prothrombin time, and activated partial thromboplastin time. Electron microscopy and x-ray microanalysis of the spleen and liver revealed electron-dense deposits in splenic macrophages, Kupffer cells, and hepatocytes composed of gadolinium, calcium, and phosphate.
Body Weight-Tumor Incidence Correlations in Long-Term Rodent Carcinogenicity Studies
Authors: Haseman Joseph K. , Young Erika , Eustis Scottie L. , Hailey J. Rick
Published: April 2009

Associations between body weight and tumor incidence and among the incidences of selected site-specific tumors were examined for more than 4,000 male and female Fischer-344 rats and B6C3F1 mice in the National Toxicology Program historical control database. Incidences of certain site-specific tumors, most notably mammary gland and pituitary gland tumors in rats and liver tumors in mice, were shown to have a strong positive correlation with 52-wk body weight. Using individual animal data, logistic regression models were derived for predicting site-specific tumor incidence as a function of 52-wk body weight, age, and other factors. This association between body weight and tumor incidence can explain many of the decreased tumor incidences observed in National Toxicology Program carcinogenicity studies. Body weight differences between dosed and control groups can also mask carcinogenic effects for those sites sensitive to body weight changes. Thus, when designing long-term rodent carcinogenicity studies, measures should be taken to minimize potential body weight differences between dosed and control groups. There were a number of small but significant negative correlations among tumor incidences, reflecting primarily the lethality of the tumors in question. None of these correlations (nor the 2 small positive correlations found) are likely to have any impact on the interpretation of experimental results. However, the high negative correlation between pituitary gland and testis tumors in male Fischer-344 rats cannot be dismissed so easily, does not reflect tumor lethality, and is currently being studied further.
Mesenchymal Tumors of the Mouse Urinary Bladder with Vascular and Smooth Muscle Differentiation
Authors: Butler William H. , Cohen Samuel H. , Squire Robert A.
Published: April 2009

Bifenthrin, a synthetic pyrethroid insecticide/miticide, has been fed to male and female Swiss Webster mice at levels of 0, 50, 200, 500, and 600 ppm in the diet for between 604 and 644 days. Tumors of the urinary bladder were observed and initially reported as leiomyosarcomas. Subsequently, the bladders were reviewed and the tumors showed a pattern of both epithelioid cells and spindle cells forming irregular vascular channels. The tumors appeared to arise from the trigone of the bladder and, in some cases, invaded the bladder wall. No metastases were recorded. The tumor is usually considered rare; however, in this study, it was commonly observed in all groups but predominantly in males. The histogenesis of the tumor is uncertain, but from its pleomorphic histological features, including smooth muscle and vascularity, it is probably derived from vascular mesenchyme.
Quantitative Relationship Between Transforming Growth Factor-Alpha and Hepatic Focal Phenotype and Progression in Female Mouse Liver
Authors: Moser Glenda J. , Wolf Douglas C. , Goldsworthy Thomas L.
Published: April 2009

Modulations in the positive hepatocyte growth factor, transforming growth factor-alpha (TGF-α) and its receptor epidermal growth factor receptor (EGFR), occur in rat and human liver tumors. The purpose of this study was to determine if TGF-α and EGFR are altered in basophilic and acidophilic preneoplastic and neoplastic liver lesions generated in DEN-initiated mice exposed to a variety of hepatocarcinogens. Female B6C3F1 mice were initiated with N-nitrosodiethylamine (DEN) and treated with hepatocarcinogenic concentrations of unleaded gasoline vapor (2,000 ppm), methyl tertiary butyl ether vapor (7,814 ppm), phenobarbital (500 ppm, diet), or chlordane (25 ppm, diet). Hepatic foci and tumors were identified and evaluated immunohistochemically with antibodies for TGF-α and EGFR. In all treatment groups, basophilic hepatic foci were negative for TGF-α immunoreactivity (554/564, 98%). In contrast, regardless of treatment, acidophilic hepatic foci were immunoreactive for TGF-α (107/108, 99%). There was no significant difference in mean hepatic labeling index as measured by the incorporation of 5-bromo-2'-deoxyuridine between foci immunoreactive and nonimmunoreactive for TGF-α. The incidence of immunoreactivity for TGF-α increased in hepatocellular tumors that were predominantly of the basophilic phenotype. Of basophilic hepatocellular adenomas, 16/81 (20%) were immunoreactive for TGF-α, while 17/29 (59%) of hepatocellular carcinomas stained positive for TGF-α. A similar increased incidence of EGFR immunoreactivity was found in basophilic hepatocellular adenomas (17/67, 25%) and carcinomas (19/28, 68%) relative to basophilic foci (11/367, 3%), suggesting an autocrine mechanism for the development of mouse liver tumors. The increased incidence of TGF-α immunoreactivity in basophilic liver tumors suggests that TGF-α is a marker of tumor progression in mouse liver. Furthermore, TGF-α modulations were dependent on phenotype rather than treatment, indicating inherent differences in the expression of TGF-α in basophilic and acidophilic hepatic lesions.
A Spontaneous Testicular Teratoma in an ICR Mouse
Authors: Tani Yoshiro , Murata Shinji , Maeda Naoyuki , Fukushige Junichiro , Hosokawa Tsunemichi
Published: April 2009

A spontaneous teratoma was detected in the left testis of a 7-wk-old male ICR (Crj:CD-1) mouse. The tumor was composed of a variety of well-differentiated tissue elements from all 3 germ layers including neuronal tissue and stratified epithelium as ectodermderived tissues, bone, cartilage, striated muscle, and adipose tissue as mesodermal tissues, and respiratory columnar epithelium as endoderm-originated tissue. No tumor metastasis was detected. It may be of congenital origin as in strain 129 mice. To the best of our knowledge, this is the first report concerning spontaneous testicular teratoma in a strain ICR mouse.
Single-Organism Model of Host Defense against Infection: A Novel Immunotoxicologic Approach to Evaluate Immunomodulatory Drugs
Authors: Herzyk Danuta J. , Ruggieri Elizabeth V. , Cunningham Lolita , Polsky Rodd , Herold Christopher , Klinkner Anne M. , Badger Alison , Kerns William D. , Bugelski Peter J.
Published: April 2009

The immunotoxicologic effects of drugs on host defense have been studied widely using various animal models of infection. Here we describe a new approach to testing host defense by using a single organism ( Candida albicans) in CBA/J mice. The model is configured to test 3 effector systems via different routes of inoculation to stimulate different effector arms of the immune response. Nonspecific immunity was evaluated by C. albicans colony-forming unit (CFU) count from the spleen at 2 hr (uptake) and ≥22 hr (clearance) following intravenous inoculation. Cell-mediated immunity was assessed by CFU count from an intramuscular injection site 6 days postinoculation. Humoral immunity was assessed by anti- Candida antibody titer, following multiple subcutaneous immunizations with C. albicans. Finally, overall immunity was evaluated following intravenous injection using survival as the endpoint. Histopathological, immunohistochemical, and electron microscopic evaluation of selected tissues revealed the involvement of the expected cell types in the different effector systems. Several immunomodulatory drugs—dexamethasone, cyclosporine, liposomal muramyltripeptide phosphatidylethanolamine, and SK&F 105685—were evaluated in the C. albicans model. Dexamethasone impaired host defense against C. albicans by suppressing all endpoints measured. Similarly, cyclosporine showed broad immunosuppressive activity, with the exception of yeast uptake from the spleen. In contrast, muramyl tripeptide-phosphatidylethanolamine enhanced all but cell-mediated immunity to C. albicans. SK&F 105685 displayed both stimulatory and inhibitory effects on immune responses to the infection. Our studies demonstrate that a single organism-based approach can be a useful method for evaluating the immunological hazards of drugs on host resistance to infection.
Invasive Pituitary Tumors in Female F344 Rats Induced by Estradiol Dipropionate
Authors: Satoh Hiroshi , Kajimura Tetsuyo , Chen Chun-Jen , Yamada Kazutaka , Furuhama Kazuhisa , Nomura Mamoru
Published: April 2009

To clarify the histopathological progression of invasive tumors in the pituitary pars distalis due to estrogen, female Fischer 344 (F344) rats were treated subcutaneously with 5 mg/animal of estradiol dipropionate (ED) once every 2 wk for 13 wk. The animals were killed serially at 2-wk intervals during the investigation. The pituitaries with surrounding tissues were examined light microscopically. At week 7, pituitary cells showed proliferation and atypia with formation of blood-filled spaces. Lesions with these characteristics were diagnosed as adenomas. At week 9 or later, neoplastic cells exhibited extensive proliferation and infiltration into the surrounding tissues, suggesting development of carcinoma. Both proliferating cell nuclear antigen (PCNA) and 5-bromo-2'-deoxyuridine (BrdU) labeling index, markers of cell proliferation, were significantly increased in animals with adenoma or carcinoma. To detect sequential changes in pituitary weight, its signal intensity was periodically monitored in identical rats by using magnetic resonance (MR) imaging. The estimated pituitary weights revealed by MR imaging were comparable to the tumor weights obtained from rats at scheduled sacrifices. These results indicate that ED possesses the potential to cause carcinoma in rat pituitary and MR imaging is an effective tool for estimating the pituitary weight.
Immunohistochemical Evaluation of Chemically Induced Rhabdomyosarcomas in Rats: Diagnostic Utility of MyoD1
Authors: Newsholme Stephen J. , Zimmerman Dawn M.
Published: April 2009

Monoclonal antibodies (mAbs) to selected muscle proteins were assessed as potential immunohistochemical markers to assist in the definitive diagnosis of poorly differentiated soft tissue sarcomas in rats. A series of 7 rat rhabdomyosarcomas (RMS) induced with nickel subsulfide were studied by light microscopy and were evaluated for immunoreactivity to desmin, vimentin, fast (type II isoform) skeletal myosin, α-actin (smooth muscle isoform), or MyoD 1 (myogenic regulatory protein) mAbs using an avidin-biotin-chromogen technique. Consecutive RMS slices were fixed in 10% neutral buffered formalin (the fixative routinely used in carcinogenicity bioassays) for periods of 3 days or 2 mo prior to paraffin embedding to determine the effect of fixation time on immunoreactivity. Desmin and vimentin mAbs bound to many cells of all tumors, but fixation for 2 mo resulted in irretrievable loss of desmin and vimentin binding. Fast myosin and α-actin mAbs bound to many cells in 1 RMS but to <1% of the cells in the remainder. MyoD1 mAb bound to tumor cell nuclei in 5/7 RMS with no loss of staining in tissue fixed for 2 mo. Results indicate that MyoD1 immunostaining, in contrast to desmin, maintains its sensitivity following prolonged formalin fixation and may be of value to distinguish RMS from other soft tissue sarcomas in the rat.
A Double-Label Technique that Monitors Sulfur Mustard Damage to Nuclei and Mitochondria of Normal Human Epidermal Keratinocytes In Vitro
Authors: Cook Jeffery R. , Van Buskirk Robert G.
Published: April 2009

Sulfur mustard and 2-chloro ethyl ethyl sulfide (CEES, a sulfur mustard analog) is known to have immediate (minutes), long-term (hours to days), and toxic effects on human skin. Research was directed toward developing a single in vitro assay that might reflect both these short-term and long-term effects of this vesicating agent on normal human epidermal keratinocytes (NHEK) in vitro. Such an assay system would be useful in identifying and developing sulfur mustard therapeutic agents. NHEK were exposed to the monofunctional sulfur mustard analog 2-chloro ethyl ethyl sulfide for a variety of times. The effects of CEES on NHEK nuclei were assessed using the membrane-permeable SYTO nuclear stains, whereas the effects of CEES on NHEK metabolism were determined by using the nontoxic mitochondria dye Alamar blue. CEES enhanced SYTO binding in a concentration-dependent manner to the nucleus immediately subsequent to a 2-hr exposure, whereas CEES had relatively little effect on metabolic activity at this time. Fifteen to 36 hr subsequent to CEES exposure, however, Alamar blue revealed a robust, sulfur mustard-dependent effect on mitochondrial activity. To determine if both these indicator dyes could be used simultaneously, NHEK were exposed to CEES and stained with the SYTO nuclear stain 2 hr subsequent to exposure. This procedure was followed by assay of the same cell cultures with Alamar blue at 36 hr subsequent to initial CEES exposure. The data indicate that this nuclear/mitochondrial double-label technique can be used to monitor the short- and long-term effects of sulfur mustard on the same culture of NHEK.
Congenital Intrahepatic Arteriovenous Fistulae in a Young Beagle Dog
Authors: Yoshizawa Katsuhiko , Oishi Yuji , Matsumoto Masahiro , Fukuhara Yoshifumi , Makino Natsuyo , Noto Takahisa , Fuj Toshiyuki
Published: April 2009

Congenital intrahepatic arteriovenous fistulae, a rare hepatic vascular anomaly, in an 8-mo-old female beagle dog was investigated. The animal showed anorexia, repeated vomiting, hemorrhagic diarrhea, and jaundice for approximately 2 wk. There was mild to severe increase of serum alkaline phosphatase, glutamic-oxalacetic transaminase, glutamic pyruvic transaminase, total cholesterol, total bilirubin, and γ-glutamyl transpeptidase. Macroscopically, the main abdominal organs showed hemorrhagic edema together with bloody ascites. Other characteristic findings were severe hepatic atrophy (right medial, quadrate, left medial, and lateral lobes) with multiple vascular cysts and compensatory hypertrophy of the other lobes. The cystic vessels seemed to extend from the proper hepatic arteries and their branches but were indistinguishable from the portal vein. Histopathologically, the atrophied hepatic lobes were characterized by wide, fibrous septa containing severe hyperplasia and anastomosis of the arteriolae and venulae and proliferation of bile ducts.
Secondary Polycythemia in Male B6C3F1 Mice with Spontaneously Occurring Hepatocellular Carcinomas
Authors: Horinouchi Akira , Hayashi Shim-Mo , Ando Takao , Nonoyama Takashi
Published: April 2009

The purpose of this study was to investigate the cause of polycythemia occurring in control male B6C3F, mice with hepatocellular carcinomas from 2-yr carcinogenicity studies. Erythrocyte counts and plasma erythropoietin levels in these mice were significantly increased compared to those in nontumor-bearing mice. Hepatocellular carcinomas in the mice were well differentiated, and the neoplastic hepatocytes contained either or both of 2 types of intracytoplasmic inclusion bodies; one was relatively large and weakly eosinophilic (pale inclusion body), while the other was relatively small and strongly eosinophilic (globular inclusion body). The pale eosinophilic inclusions but not the globular ones were immunohistochemically positive for erythropoietin. Ultrastructurally, the erythropoietin-positive inclusions were characterized by granular materials in dilated cisternae of rough endoplasmic reticulum, suggesting increased protein synthesis. Erythropoietin-negative inclusions were dense bodies that were not surrounded by a delimiting membrane. These findings indicate that polycythemia in hepatocellular carcinoma-bearing mice occurs secondary to excess synthesis and secretion of erythropoietin by neoplastic hepatocytes.
Alteration in Cell Kinetics in Control B6C3F1 Mice Infected with Helicobacter hepaticus
Authors: Nyska Abraham , Maronpot Robert R. , Eldridge Sandra R. , Haseman Joseph K. , Hailey James R.
Published: April 2009

The discovery of Helicobacter hepaticus infection, H. hepaticus hepatitis, and increased incidence of liver tumors in control males from several recent National Toxicology Program B6C3F, mouse carcinogenicity bioassays raised questions regarding the suitability of these bioassays for hazard identification. The purpose of this study was to determine if changes in cell proliferation and death at terminal sacrifice might be linked to the increased liver tumor incidences among control males. In control males, enhanced rates of hepatocyte proliferation, as assessed by immunostaining for proliferating cell nuclear antigen (PCNA), and apoptosis, as assessed from hematoxylin and eosin- and TUNEL-stained preparations, were seen in 3 bioassays with H. hepaticus hepatitis. One bioassay with H. hepaticus infection without attendant hepatitis and one bioassay without H. hepaticus or hepatitis did not have elevated rates of hepatocyte proliferation or apoptosis. There was no significant effect on PCNA cell proliferation indices or apoptosis in females. The present findings are indicative of a clear association between the presence of H. hepaticus infection with attendant hepatitis, increased cell proliferation and apoptosis, and increased incidences of hepatocellular neoplasia in males but not in females. Thus, the interpretation of liver tumor responses in H. hepaticus-infected studies is considered to be confounded in male mice. The lack of enhanced cell proliferation or hepatocellular neoplasia in control females suggests that bioassay results from females are valid for hazard identification. Furthermore, the absence of enhanced cell proliferation in lungs and kidneys of male and females suggests that neoplastic effects at these sites are not exacerbated by H. hepaticus infection.
Toxic Effects of Quinolone Antibacterial Agents on the Musculoskeletal System in Juvenile Rats
Authors: Kashida Yoko , Kato Michiyuki
Published: April 2009

Quinolone antibacterial agents have adverse effects on the musculoskeletal system in humans, consisting mainly of myalgia and arthralgia, and additionally of tendon disorders and rhabdomyolysis. The present study was conducted to examine the toxic effects of quinolones on the musculoskeletal system in juvenile rats using light microscopy, 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry and electron microscopy. Single oral administration of 900 mg/kg pefloxacin (PFLX) or levofloxacin (LVFX) was found to induce lesions in the muscle + fascia, tendon + sheath, and synovial membrane, in addition to articular cartilage in the fore- and hindlimbs. Articular cartilage lesions were not necessarily associated with changes in the muscle, tendon, and synovial membrane, or the reverse. Among all lesions, the ankle and elbow showed the highest incidence and severity. Changes were more severe in the PFLX than in the LVFX group. Lesions in the muscle + fascia, tendon + sheath, and synovial membrane were similar and characterized by edema and increased number of mononuclear cells, many of which were positively stained with BrdU, as well as vascular endothelial cells in the Achilles tendon sheath and synovial membrane in the ankle. Electron microscopic examination revealed an increased number of fibroblasts and macrophages and collagen deposition in the matrix of the synovial membrane and tendon sheath. Capillary endothelial cells were hypertrophied, increased in number, and stratified. These results suggest that quinolones have toxic potentials in the muscle, tendon, and synovial membrane in addition to articular cartilage, and that local vascular hyperpermeability may contribute to the development of these lesions.
Evaluation of the Eμ-pim-1 Transgenic Mouse Model for Short-Term Carcinogenicity Testing
Authors: Van Kreijl Coen F. , Willemien Van Der Houven Van Oordt C. , Dinant Kroese E. , Kryspin Sørensen Ilona , Breuer Marco L. , Storer Richard D.
Published: April 2009

The value of the chronic rodent carcinogenicity assay in adequately predicting cancer risk in humans has become a matter of debate over the past few years. Therefore, more rapid and accurate alternative tests are urgently needed. Transgenic mouse models, those harboring genetic changes that are relevant to the multistage cancer process, may provide such alternative tests. Transgenic Eμ- pim-1 mice, developed by Berns and coworkers in 1989, contain the pim-1 oncogene, which is expressed at elevated levels in their lymphoid compartments. As a result, these mice are predisposed to the development of T-cell lymphomas. Because of the low incidence of spontaneous tumors and the increased sensitivity to N-ethyl- N-nitrosourea-induced carcinogenesis, Eμ- pim-1 mice were suggested to be one of the first potential and attractive candidates to be used in short-term carcinogenicity testing. In the present article, the results from 2 recent short-term assays (with mitomycin C and x-rays) are briefly presented, together with a review of all 11 performed bioassays and their corresponding histopathologic and molecular data. The overall results allow the first evaluation of the Eμ- pim-1 mouse model with regard to its usefulness in short-term carcinogenicity testing. It has been shown that the model is primarily suitable as a sensitive short-term assay for genotoxic carcinogens that not only induce (at least) gene mutations and/or large deletions and rearrangements but that also sufficiently target the lymphoid system. However, the Eμ- pim-1 mice lack sufficient sensitivity to justify their routine use in short-term carcinogenicity testing in general.
Development of Fumonisin-Induced Hepatotoxicity and Pulmonary Edema in Orally Dosed Swine: Morphological and Biochemical Alterations
Authors: Gumprecht Laura A. , Beasley Val R. , Weigel Ronald M. , Parker Helen M. , Tumbleson Mike E. , Bacon Charles W. , Meredith Filmore I. , Haschek Wanda M.
Published: April 2009

The fumonisin (FB) mycotoxins induce liver injury in all species but induce fatal pulmonary edema (PE) only in pigs. They inhibit ceramide synthase in the sphingolipid biosynthetic pathway. To study the pathogenesis of PE, we examined the early events in the development of FB-induced PE and hepatotoxicity in pigs. Pigs were fed FB-contaminated culture material at 20 mg fumonsin B1 (FB 1)/kg body weight/day. Groups of 4 pigs were to be euthanatized on 0, 1, 2, 3, 4, or 5 days after initial exposure to FB or when PE developed. Pigs developed PE beginning on day 3; none survived beyond day 4. Progressive elevations in hepatic parameters, including serum enzymes, bile acids, total bilirubin, and histologic changes, began on day 2. Early histologic changes in the lung (day 2) consisted of perivascular edema followed by interlobular and peribronchial edema. Ultrastructurally, alveolar endothelial cells contained unique accumulations of membranous material in the cytocavitary network beginning on day 2. Marked elevations in sphinganine, sphingosine, and their ratio began on day 1 for all tissues whether affected morphologically (lung, liver) or not (kidney, pancreas). The membranous material in endothelial cells may be accumulations of sphingoid bases with damage to the cytocavitary network. Thus, FB induces early elevations in sphingolipids and hepatic injury, followed by alveolar endothelial damage, which may be the critical event in the pathogenesis of PE in pigs.
Vacuolation in Renal Tubular Epithelium of Cd-1 Mice: An Incidental Finding
Authors: Johnson R.C. , Dovey-Hartman B.J. , Syed J. , Leach M.W. , Frank D.W. , Sinha D.P. , Mirro E.J. , Little J.M. , Halliwell W.H.
Published: April 2009

Prominent cytoplasmic vacuoles were observed in renal tubular epithelial cells of the outer medulla in several kidneys from test article-dosed mice (Crl:CD®-1 (ICR)BR VAF/PLUS™) during routine light microscopic (LM) examination. Because the vacuolar change was detected infrequently and was not found in any control mice from that study, it was not clear whether the vacuolation represented a drug-induced change. To address this question, kidney sections from mice from multiple unrelated studies were examined by LM for similar vacuolar changes. Vacuolation was seen by LM in 2.3% of the control and 2.8% of the test article-dosed mice. Transmission electron microscopy (TEM) was also performed on kidneys with prominent light microscopic vacuoles in 5 control mice and 2 test article-dosed mice to further characterize the vacuoles. Ultrastructurally, the vacuoles contained fibrillar and finely stipled granular material or membranous whorls. Kidneys from control mice lacking light microscopic evidence of vacuolation had smaller vacuoles containing similar material when examined by TEM. Because vacuoles were present in both control mice and test article-dosed mice, it was concluded that the vacuoles were incidental and unrelated to compound administration. These studies also demonstrated that vacuoles can be expected to be observed by LM examination in 2-3% of Crl:CD®-1 (ICR)BR VAF/PLUS™ mice.
Review Article: Apoptosis in the Kidney
Authors: Davis Myrtle A. , Ryan Dara H.
Published: April 2009

Apoptosis is a highly regulated mechanism of cell death. Although apoptosis has a functional role in normal development and tissue homeostasis, aberrant triggering of the process by toxicants may lead to abnormal function or disease. Low level exposures to toxicants that induce apoptosis in kidney may therefore create a critical disturbance in kidney homeostasis, contributing to renal neoplasia or renal disease. In this report, we review the involvement of apoptosis in normal kidney development and in renal disease and discuss some of the toxicants and molecular factors involved in regulation of the process in renal cells.
Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines
Authors: Anderson I. M. , Nutt D. J. , Deakin J. F. W.
Published: April 2009

A revision of the British Association for Psychopharmacology guidelines for treating depressive disorders with antidepressants was undertaken in order to specify the scope and target of the guidelines and to update the recommendations based explicitly on the available evidence. A consensus meeting, involving experts in depressive disorders and their treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from participants and interested parties. A literature review is given which identifies the quality of evidence followed by recommendations, the strength of which are based on the level of evidence. The guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing, management when initial treatment fails, continuation treatment, maintenance treatment to prevent recurrence and stopping treatment.
Double-blind comparison of venlafaxine and amitriptyline in outpatients with major depression with or without melancholia
Authors: Gentil Valentim , Kerr-Correa Florence , Moreno Ricardo , Busnello Ellis D’Arrigo , de Campos João Alberto , Juruena Mario Francisco , Lafer Beny , Moreno Doris Hupfeld , Rosa Lucena de Cassia Rodrigues , Tiosso Ana , Benedictis Eliana
Published: April 2009

The purpose of this study was to compare the efficacy and tolerability of venlafaxine and amitriptyline in outpatients with major depression with or without melancholia. This was an 8-week, multicentre, randomized, double-blind, parallel-group comparison of venlafaxine and amitriptyline. Outpatients with DSM-IV major depression, a minimum score of 20 on the 21-item Hamilton Depression Rating Scale (HAM D), and depressive symptoms for at least 1 month were eligible. Patients were randomly assigned to venlafaxine or amitriptyline, both drugs titrated to a maximum of 150 mg/day until study day 15. The primary efficacy variables were the final on-therapy scores on the HAM-D, Montgomery-Asberg Depression Rating Scale and Clinical Global Impression severity scales. Data were evaluated on an intent-to-treat basis using the LOCF method. One hundred and 16 patients were randomized, and 115 were evaluated for efficacy. Both drugs showed efficacy in the treatment of depression with or without melancholia. No significant differences were noted between treatments for any efficacy parameter. However, significantly (p < 0.05) more patients in the amitriptyline group had at least one adverse event. These results should support the efficacy and tolerability of venlafaxine in comparison with amitriptyline for treating major depression with or without melancholia.
Allopurinol for refractory aggression and self-inflicted behaviour
Authors: Lara Diogo R. , Belmonte-de-Abreu Paulo , Souza Diogo O.
Published: April 2009

The impairment of the purinergic system, characterized by reduced adenosinergic activity, has been implicated in the neurobiology of aggressive behaviour. Since there are no direct adenosine agonists available for human use, inhibition of purine degradation by allopurinol was conceived as a possible strategy. We report two cases of adults with refractory aggressive behaviour due to a neurological condition (one mainly with self-inflicted behaviour) with dramatic response to therapy with allopurinol, 300 mg/day p.o. These preliminary results reinforce the involvement of the purinergic system in the neurobiology of aggression, warranting further testing of allopurinol as a new treatment for aggressive and self-inflicted behaviours.
Serotonin autoreceptor function and antidepressant drug action
Authors: Hjorth S. , Bengtsson H. J. , Kullberg A. , Carlzon D. , Peilot H. , Auerbach S. B.
Published: April 2009

This article briefly summarizes, within the context of a brief review of the relevant literature, the outcome of our recent rat microdialysis studies on (1) the relative importance of serotonin (5-HT)1Aversus 5-HT1Bautoreceptors in the mechanism of action of 5-HT reuptake blocking agents, including putative regional differences in this regard, and (2) autoreceptor responsiveness following chronic SSRI administration. First, our data are consistent with the primacy of 5-HT1Aautoreceptors in restraining the elevation of 5-HT levels induced by SSRIs, whereas nerve terminal 5-HT1Bautoreceptors appear to have an accessory role in this regard. Second, there is an important interplay between cell body and nerve terminal 5-HT autoreceptors, and recent findings suggest that this interplay may potentially be exploited to obtain regionally preferential effects on 5-HT neurotransmission in the central nervous system, even upon systemic drug administration. In particular, emerging data suggest that somatodendritic 5-HT1Aautoreceptorand nerve terminal 5-HT1Bautoreceptor-mediated feedback may be relatively more important in the control of 5-HT output in dorsal raphe-frontal cortex and median raphe-dorsal hippocampus systems, respectively. Third, 5-HT autoreceptors evidently retain the capability to limit the 5-HT transmission-promoting effect of SSRIs after chronic treatment. Thus, although the responsiveness of these sites is probably somewhat reduced, residual autoreceptor capacity still remains an effective restraint on large increases in extracellular 5-HT, even after prolonged treatment. If a further increase in extracellular 5-HT is crucial to the remission of depression in patients responding only partially to prolonged administration of antidepressants, then sustained adjunctive treatment with autoreceptor-blocking drugs may consequently prove useful in the long term.
A double-dissociation of behavioural and event-related potential effects of two benzodiazepines with similar potencies
Authors: Pompéia S. , Bueno O. F. A. , Lucchesi L. M. , Manzano G. M. , Galduróz J. C. F. , Tufik S.
Published: April 2009

This study was designed to explore the role of benzodiazepine affinity to benzodiazepine binding site on acute psychomotor, subjective and memory effects, as well as auditory Event Related Potential (ERP) latencies, in healthy volunteers. Two benzodiazepines with similar affinity to benzodiazepine binding sites, or potency, were compared: the atypical compound lorazepam (2.0 mg), which has been reported to impair priming, and a standard benzodiazepine, flunitrazepam (0.6 mg, 0.8 mg, 1.0 mg). The study followed aplacebo-controlled, double-blind, parallel-group design. Sixty subjects completed a test battery before treatment and at theoretical peak plasma concentration of drugs. Lorazepam and 1.0 mg of flunitrazepam led to comparable alterations on psychomotor, subjective and auditory episodic memory measures. A double-dissociation was found for lorazepam and the equipotent dose of flunitrazepam (1.0 mg): lorazepam was more deleterious than flunitrazepam in time taken to identify fragmented shapes. Lorazepam also impaired direct and indirect stem-completion in comparison to placebo, but this effect was abolished when time to identify shapes was used as a covariate. By contrast, 1.0 mg of flunitrazepam prolonged auditory ERP latencies to a greater extent than lorazepam. High affinity to the benzodiazepine binding sites does not seem to explain the consistent lorazepam-induced impairment of indirect stem-completion. Differences in impairment profile between the benzodiazepines employed may relate to the modality (visual or not) of the tasks used.
Acute effects of LI 160 (extract of Hypericum perforatum, St John's wort) and two of its constituents on neuroendocrine responses in the rat
Authors: Franklin M. , Chi J. D. , Mannel M. , Cowen P. J.
Published: April 2009

Extracts of Hypericum perforatum (St John's wort), such as LI 160, which are effective antidepressants have several active constituents. Their mode of action in depression, however, is unclear. In the present investigation, we assessed the effect of equivalent doses of LI 160 and two of its components, hypericin and hyperforin on serotonin (5-HT) and dopamine (DA)-mediated neuroendocrine responses in the rat. LI 160, hypericin and hyperforin significantly and equivalently increased plasma corticosterone. This effect was blocked by ketanserin but not WAY-100635, suggesting mediation via 5-HT2 receptors. LI 160 also lowered plasma prolactin and prevented the increase in plasma prolactin following haloperidol administration. Hyperforin had a similar but somewhat less pronounced effect. We conclude that LI 160, hypericin and hyperforin all increase 5-HT-mediated corticosterone release while LI 160 enhances DA-mediated inhibition of prolactin release. Hyperforin may contribute to the facilitatory effect of LI 160 on DA function, but hypericin does not.
D2 receptor occupancy under recommended and high doses of olanzapine: an iodine-123-iodobenzamide SPECT study
Authors: Meisenzahl E. M. , Dresel S. , Frodl T. , Schmitt G. J. E. , Preuss U. W. , Rossmüller B. , Tatsch K. , Mager T. , Hahn K. , Möller H. -J.
Published: April 2009

The aim of this study was to compare the degree of striatal dopamine D2receptor availability in patients treated with recommended (5–20 mg, mean dose 11.9 ± 6.3 mg daily) and higher doses (25–40 mg, mean 32.1 ± 5.6 mg daily) of the novel antipsychotic drug olanzapine by means of [123I] IBZM Single photon emission computed tomography (SPECT). The results were compared to those of a group of 10 untreated, healthy, age- and sex-matched controls. The degree of dopamine D2receptor occupancy in the patient group was correlated with the presence of extrapyramidal symptoms (EPS). A total of 20 patients who met the DSM III R criteria for schizophrenia or schizoaffective disorder received a clinically effective antipsychotic monotherapy with olanzapine. The mean daily dose of olanzapine ranged from 0.05–0.6 mg/kg body weight. The dopamine D2receptor binding was reduced in all patients treated with olanzapine. Specific IBZM binding expressed as the [STR-BKG]/BKG ratio ranged from 0.13–0.61 (healthy controls 0.95). The D2receptor availability revealed an exponential dose–response relationship (r=–0.85, p< 0.001). The frequency of EPS induced by olanzapine was considerably lower. Only one patient, treated with 40 mg olanzapine, suffered from severe EPS symptoms and had to be given biperiden. There were no significant differences in the presence of EPS symptoms between patients with recommended doses and those with higher doses of olanzapine.
Individual differences in mood reactions to d-amphetamine: a test of three personality factors
Authors: Corr Philip J. , Kumari Veena
Published: April 2009

Individual differences in self-reported mood following either 5 mg or 10 mg d-amphetamine challenge were examined in order to test the modifying role of three factors of personality, viz., the Eysencks' psychoticism, Cloninger's novelty seeking, and Depue and Collins' extraversion. In a double-blind study, mood measures (energetic arousal, tense arousal, and hedonic tone) were taken immediately following a single-dose of d-amphetamine and then again after 90 min. The results showed significant psychoticism × d–amphetamine interactions for both drug doses: d-amphetamine increased energetic arousal and hedonic tone, and reduced tense arousal, only in low psychoticism individuals; in high psychoticism individuals, it led to lowered energetic arousal and hedonic tone, and increased tense arousal. Neither novelty seeking nor extraversion modified the effects of d-amphetamine. These data suggest a link between psychoticism and dopaminergic functioning, although they do not rule out the involvement of other transmitter systems (e.g. noradrenergic). In common with other studies, such findings point to the important role that well-established factors of personality play in accounting for individual differences in reactions to psychoactive drugs. It is concluded that the routine inclusion of personality measures in future psychopharmacological studies may help to refine the characterization of drug effects.
Suicide and schizophrenia
Authors: Siris Samuel G.
Published: April 2009

Suicide and suicide attempts occur at a significantly greater rate in schizophrenia than in the general population. Common estimates are that 10% of people with schizophrenia will eventually have a completed suicide, and that attempts are made at two to five times that rate. Demographically associated with suicidality in schizophrenia are being young, being early in the course of the illness, being male, coming from a high socioeconomic family background, having high intelligence, having high expectations, not being married, lacking social supports, having awareness of symptoms, and being recently discharged from the hospital. Also associated are reduced self-esteem, stigma, recent loss or stress, hopelessness, isolation, treatment non-compliance and substance abuse. Clinically, the most common correlates of suicidality in schizophrenia are depressive symptoms and the depressive syndrome, although severe psychotic and panic-like symptoms may contribute as well. This review specifically explores the issue of depression in schizophrenia, in relation to suicide, by organizing the differential diagnosis of this state and highlighting their potentially treatable or correctable causes. This differential diagnosis includes both acute and chronic disappointment reactions, the prodrome of an acute psychotic episode, neuroleptic induced akinesia and akathisia, the possibility of direct neuroleptic-induced depression, negative symptoms of schizophrenia, and the possible co-occurrence of an independent depressive diathesis. The potential beneficial roles of ‘atypical’ antipsychotic agents, including both clozapine and more novel agents, and adjunctive treatment with other psychopharmacological medications are considered, and the important roles of psychosocial factors and interventions are recognized.
Pharmacokinetics of valproic acid in patients with bipolar disorder
Authors: Vasudev Kamini , Das Saurendra , Goswami Utpal , Tayal Girish
Published: April 2009

The pharmacokinetics of valproic acid (VPA) were studied in nine patients with bipolar disorder who were receiving VPA as prophylactic therapy, following the full daily dose (400–1500 mg), on which the patients had been maintained for at least the past 3 months. The data from our study showed that the pharmacokinetics of valproate followed a two compartment open model. A time lag of 1–2 h was observed in each patient, followed by rapid absorption, with the peak concentrations being recorded approximately 4 h after drug administration. The average 12 h trough concentration was found to be 54.73 ± 11.96 µg/ml. The plasma level decline was biphasic with a terminal half-life of 14.2 ± 6.39 h. Total plasma clearance was 0.095 ± 0.035 ml/min/kg. The steady-state apparent volume of distribution was found to be 0.11 ± 0.05 l/kg. A positive correlation (r= 0.69) was found between the dose (mg/kg) and steady-state serum concentration (Css) of VPA and all patients, except one, had their Css above 50 µg/ml. Most of the pharmacokinetic parameters in this study involving euthymic bipolar patients on long-term VPA monotherapy were found to be in agreement with those reported in literature on seizure disorder patients on similar regime; however, the plasma elimination half-life appears to be prolonged in bipolar patients.