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An 83-year-old male with a 55-year history of Crohn's disease, ileocecectomy 40 years prior, and naturopathic treatment for 25 years, presented with nausea, vomiting, and abdominal pain. Computed tomography of abdomen and pelvis demonstrated partial small intestinal obstruction and a 4.4-cm solid left renal mass. After 3 months of recurrent intestinal obstruction and development of a pericolonic abscess, resection of the ileocolonic anastomosis, abscess, and partial nephrectomy were performed. Histopathology demonstrated chronic active enteritis with fistula tract formation, consistent with Crohn's disease, and moderately differentiated small intestinal adenocarcinoma extending from mucosa into subserosa. A submucosal intestinal lymph node-like structure containing adenocarcinoma demonstrated endothelial venules, open marginal and intermediate sinuses, multiple polarized germinal centers, and partial capsule, consistent with an ectopic lymph node, also called a tertiary lymphoid organ. Twenty mesenteric lymph nodes were negative for carcinoma. The renal mass was a papillary renal cell carcinoma, Stage I. Intestinal tertiary lymphoid organs form in chronic immune activation and have variable structures ranging from simple B and T cell clusters to organized groups with high endothelial venules and lymphatic vessels. Encapsulation of tertiary lymphoid organs is rare, with some sources claiming this entity is never encapsulated. To our knowledge, this is the first report of small intestinal adenocarcinoma involving a submucosal encapsulated tertiary lymphoid organ, the prognostic significance of which is uncertain. We suggest increased awareness of intestinal tertiary lymphoid organs as an entity and further studies to delineate the effect their involvement by adenocarcinoma imparts on survival. [ABSTRACT FROM AUTHOR]

Porphyrinogenic compounds are known to induce porphyria-mediated hepatocellular injury and subsequent regenerative proliferation in rodents, ultimately leading to hepatocellular tumor induction. However, an appropriate in vivo experimental model to evaluate an effect of porphyrinogenic compounds on human liver has not been fully established. Recently, the chimeric mouse with humanized liver (PXB mice) became widely used as a humanized model in which human hepatocytes are transplanted. In the present study, we examined the utility of PXB mice as an in vivo experimental model to evaluate the key events of the porphyria-mediated cytotoxicity mode of action (MOA) in humans. The treatment of PXB mice with 5-aminolevulinic acid, a representative porphyrinogenic compound, for 28 days caused protoporphyrin IX accumulation, followed by hepatocyte necrosis, increased mitosis, and an increase in replicative DNA synthesis in human hepatocytes, indicative of cellular injury and regenerative proliferation, similar to findings in patients with porphyria or experimental porphyria models and corresponding to the key events of the MOA for porphyria-mediated hepatocellular carcinogenesis. We conclude that the PXB mouse is a useful model to evaluate the key events of the porphyria-mediated cytotoxicity MOA in humans and suggest the utility of PXB mice for clarifying the human relevancy of findings in mice. [ABSTRACT FROM AUTHOR]

To begin, I wish to thank the Academy of Toxicological Sciences for bestowing this honor on me. I have had a rewarding career in basic research and clinical medicine, beginning with research in high school and always planning on becoming a physician. I have had the good fortune of having outstanding mentors, wonderful parents, and a supportive and intuitive wife and family. This article provides a brief overview of some of the events of my career and individuals who have played a major role, beginning with the M.D./Ph.D. program at the University of Wisconsin, pathology residency and faculty at St. Vincent Hospital, Worcester, Massachusetts, a year as visiting professor at Nagoya City University, and my career at the University of Nebraska Medical Center since 1981. This could not have happened without the strong input and support from these individuals, the numerous students, residents and fellows with whom I have learned so much, and the more than 500 terrific collaborators. [ABSTRACT FROM AUTHOR]

Several chemicals and pharmaceuticals increase the incidence of hemangiosarcomas (HSAs) in mice, but the relevance to humans is uncertain. Recently, canine HSAs were identified as a powerful tool for investigating the pathogenesis of human HSAs. To characterize the cellular phenotype of canine HSAs, we evaluated immunoreactivity and/or messenger RNA (mRNA) expression of markers for hematopoietic stem cells (HSCs), endothelial cells (ECs), a tumor suppressor protein, and a myeloid marker in canine HSAs. Neoplastic canine cells expressed EC markers and a myeloid marker, but expressed HSC markers less consistently. The canine tumor expression results were then compared to previously published immunoreactivity results for these markers in human and mouse HSAs. There are 2 noteworthy differences across species: (1) most human HSAs had HSC marker expression, indicating that they were comprised of tumor cells that were less differentiated than those in canine and mouse tumors; and (2) human and canine HSAs expressed a late-stage EC maturation marker, whereas mouse HSAs were negative, suggesting that human and canine tumors may retain greater differentiation potential than mouse tumors. These results indicate that HSA development is variable across species and that caution is necessary when discussing translation of carcinogenic risk from animal models to humans. [ABSTRACT FROM AUTHOR]

Crystalluria can involve the kidney and lower urinary tract, can produce acute and chronic effects, and occurs in all mammalian species. Most commonly urinary crystals contain calcium. Numerous other endogenous and exogenous substances can produce crystalluria. Crystals are identified in kidneys of many species, up to 100% in certain rat strains. More severe renal disease (acute tubular necrosis and chronic renal disease) can be secondary to crystal accumulation, such as observed with melamine–cyanuric acid in cats and dogs. Aggregation of crystals leads to calculi that act as urothelial abrasives with consequent regenerative proliferation. Accumulation in the kidney pelvis or bladder can lead to partial or complete obstruction and hydronephrosis. Long-term presence of urinary tract calculi in rodents leads to increased risk of urothelial tumors, but not in humans. Crystals in the lower urinary tract can act as irritants in rodents, but not in humans. It is critical that specific procedures are followed to optimize the presence of crystals in urine for diagnosis, including not fasting the animals. Numerous factors have been identified which can enhance or inhibit crystal formation. Extrapolation from animals for the threshold toxicity of crystals/calculi is appropriate but is not relevant for cancer risk assessment. [ABSTRACT FROM AUTHOR]

The article reports on recommendations from the Federal Bar Council Committee on Labor Law concerning sweetheart contracts. Sweetheart arrangements, which can also take the form of "paper locals," are a threat to legitimate collective bargaining and union movements. There is a discussion of Title 29, United States Code, section 186, which was enacted as section 302 of the Labor Management Relations Act of 1947 and is linked to the Taft-Hartley Act. State court injunctions and sweetheart unions are mentioned, as well as how to attack sweetheart contracts.

The article reports on the recommendations of the Committee on Labor Law of the Federal Bar Council concerning defamation and industrial relations. The discussion includes the effect of federal law in defamation lawsuits, the purpose of defamation cases and their impact on society, and the dangers and risks in defamation suits. The group concludes that damages for defamation should not be allowed in a class of cases where the alleged remark occurred during an organizational campaign, collective bargaining negotiation, or contract administration, was made only to employees, and focused only on working or treatment of employees. The right of reply is mentioned.

Chronic progressive nephropathy (CPN) occurs commonly in rats, more frequently and severely in males than females. High-grade CPN is characterized by increased layers of the renal papilla lining, designated as urothelial hyperplasia in the International Harmonization of Nomenclature and Diagnostic Criteria classification. However, urothelium lining the pelvis is not equivalent to the epithelium lining the papilla. To evaluate whether the epithelium lining the renal papilla is actually urothelial in nature and whether CPN-associated multi-cellularity represents proliferation, kidney tissues from aged rats with CPN, from rats with multicellularity of the renal papilla epithelium of either low-grade or marked severity, and from young rats with normal kidneys were analyzed and compared. Immunohistochemical staining for uroplakins (urothelial specific proteins) was negative in the papilla epithelium in all rats with multicellularity or not, indicating these cells are not urothelial. Mitotic figures were rarely observed in this epithelium, even with multicellularity. Immunohistochemical staining for Ki-67 was negative. Papilla lining cells and true urothelium differed by scanning electron microscopy. Based on these findings, we recommend that the epithelium lining the papilla not be classified as urothelial, and the CPN-associated lesion be designated as vesicular alteration of renal papilla instead of hyperplasia and distinguished in diagnostic systems from kidney pelvis urothelial hyperplasia. [ABSTRACT FROM AUTHOR]

Background: Abnormal scaphoid alignment after fracture is used as an indication for fixation. Acceptable alignment after reduction and fixation of scaphoid fractures is not well defined. We systematically reviewed the literature to identify how scaphoid malunion is currently defined and by what parameters. Methods: A systematic review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Multiple databases were searched for studies published in the English language that reported on outcomes after scaphoid malunion and included measurements to define malunions. Radiographic scaphoid measurement parameters were collected. Clinical outcome measures recorded included grip strength, wrist range of motion, and patient-reported outcome measures. Study quality was analyzed using the Methodological Index for Non-Randomized Studies (MINORS) criteria. Descriptive summaries of the studies are presented. Results: The initial search yielded 1600 articles. Ten articles (161 participants, 93% males, mean age = 28.3 + 6.3 years, mean MINORS score = 10.2 + 1.6) were included and analyzed. Scaphoid malunion was defined if the lateral intrascaphoid angle (LISA) was >45° (3 articles), LISA >35° (1 article), and height to length ratio >0.6 (3 articles). Four out of 5 studies found no significant associations between patient outcomes and degree of scaphoid malunion measured on imaging. Conclusions: There is a lack of consensus for defining scaphoid malunion on imaging and absence of correlation between findings on imaging and patient outcomes. Future studies defining scaphoid malunion should be appropriately powered, incorporate measures of intrarater and interrater reliabilities for all reported imaging measurements, and utilize validated patient-reported outcome measures to reflect that malunion is associated with inferior outcomes meaningful to patients. [ABSTRACT FROM AUTHOR]

Dr Gordon Hard, of Tairua, New Zealand, a preeminent international toxicology thought leader and international consultant in toxicologic pathology of the kidney, passed on November 22, 2021. He was a key player in shaping and developing the global field of toxicologic pathology and the role of toxicologic pathology in risk assessment of environmental chemicals and pharmaceuticals. [ABSTRACT FROM AUTHOR]

Increased cell proliferation is a central key event in the mode of action for many non-genotoxic carcinogens, and quantitative cell proliferation data play an important role in the cancer risk assessment of many pharmaceutical and environmental compounds. Currently, there is limited unified information on assay standards, reference values, targeted applications, study design issues, and quality control considerations for proliferation data. Here, we review issues in measuring cell proliferation indices, considerations for targeted studies, and applications within current risk assessment frameworks. As the regulatory environment moves toward more prospective evaluations based on quantitative pathway-based models, standardization of proliferation assays will become an increasingly important part of cancer risk assessment. To help address this development, we also discuss the potential role for proliferation data as a component of alternative carcinogenicity testing models. This information should improve consistency of cell proliferation methods and increase efficiency of targeted testing strategies. [ABSTRACT FROM AUTHOR]

Inorganic arsenic (arsenite and arsenate) at high exposures is a known human carcinogen, inducing tumors of the urinary bladder, skin, and lungs. In two experiments, we examined the urothelial proliferative effects of treatment with 173 ppm sodium arsenite (100 ppm arsenic) in the drinking water for 6 and 24 hr, and 3, 7, and 14 days in female F344 rats and 43.3 ppm sodium arsenite (25 ppm arsenic) in female C57BL/6 wild-type and arsenic (+3 oxidation state) methyltransferase knockout (As3mt KO) mice that are unable to methylate arsenicals. In the rat and both mouse genotypes, scanning electron microscopy showed cytotoxic urothelial changes as early as 6 hr after the start of arsenic exposure. The severity of AsIII-induced cytotoxic urothelial changes increased over time in the rat and in the As3mt KO mouse. Light microscopy showed an increase in urothelial hyperplasia in the rat. No significant increases in bromodeoxyuridine-labeling index were observed. The data support the hypothesis that the sequence of events in the mode of action for urothelial effects of orally administered inorganic arsenic in the rat and mouse involves superficial cytotoxicity with consequent regenerative increased cell proliferation similar to the findings associated with the administration of dimethylarsinic acid (DMAV) in rats. [ABSTRACT FROM PUBLISHER]

Dr Hard received a BSc from the University of Auckland in 1955 and a Bachelor of Veterinary Science in 1959 from the University of Sydney (Australia). Dr Hard was multitalented, in his early years playing college soccer (University of Sydney) and semiprofessional soccer (Melbourne InterVarsity Football) in Australia. Graph Dr Gordon Hard, of Tairua, New Zealand, a preeminent international toxicology thought leader and international consultant in toxicologic pathology of the kidney, passed on November 22, 2021. [Extracted from the article]

It is unclear whether the process of spontaneous and chemically induced hemangiosarcoma and hemangioma formation in mice involves the transformation of differentiated endothelial cells (ECs) or recruitment of multipotential bone marrow–derived hematopoietic stem cells or endothelial progenitor cells (EPCs), which show some degree of endothelial differentiation. In the present study, immunohistochemical staining for hematopoietic stem cell markers (CD45 and CD34), EC markers (vascular endothelial growth factor receptor 2 [VEGFR2], CD31, and factor VIII–related antigen), and a myeloid lineage marker (CD14) was employed to better define the origin of hemangiosarcomas and hemangiomas in mice. Staining was negative for CD45, factor VIII–related antigen, and CD14 and positive for CD34, VEGFR2, and CD31, indicating that mouse hemangiosarcomas and hemangiomas are composed of cells derived from EPCs expressing CD34, VEGFR2, and CD31 but not factor VIII–related antigen. The lack of CD45 expression suggests that mouse vascular tumors may arise from EPCs that are at a stage later than hematopoietic stem cells. Since factor VIII–related antigen expression is known to occur later than CD31 expression in EPCs, our observations may indicate that these tumor cells are arrested at a stage prior to complete differentiation.  In addition, myeloid lineage cells do not appear to contribute to hemangiosarcoma and hemangioma formation in mice. [ABSTRACT FROM PUBLISHER]

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists and PPARγ/α dual agonists are used in the treatment of type 2 diabetes mellitus and hyperlipidemias. In carcinogenicity studies, some of these agonists induced hemangiomas/hemangiosarcomas in mice, but not in rats. We hypothesized that increased endothelial cell (EC) proliferation may be involved in the mechanism of PPAR agonist–induced vascular tumors in mice. We previously showed that the sarcomagenic PPARγ agonist troglitazone (TG) increased EC proliferation in brown and white adipose tissue and liver in mice at sarcomagenic doses (400 and 800 mg/kg) after four weeks of treatment. In vitro, TG had a mitogenic effect on mouse microvascular mouse ECs by increasing cell proliferation and survival. The current studies showed that treatment of mouse ECs in vitro induced alterations in proliferation pathway gene expression, especially the expression of insulin-like growth factor-1, but had no effect on mouse oxidative stress pathways. In vivo, treatment with vitamin E did not inhibit TG-induced EC proliferation in liver and adipose tissue. In addition, no hypoxic effect was detected in adipose tissue of TG-treated mice; however, TG had a minor effect on hepatocellular hypoxia. These results provide additional evidence supporting a direct mitogenic effect in the mode of action of TG-induced hemangiosarcomas in mice. [ABSTRACT FROM PUBLISHER]

The two-year rodent bioassay remains the mainstay for carcinogenicity testing, although numerous difficulties have been identified. Fundamentally, a chemical can increase the risk of cancer (1) by damaging DNA directly (DNA reactive) or (2) indirectly by increasing the number of DNA replications (non—DNA reactive). Mechanistic research has identified numerous precursor lesions in the sequence of key events necessary for neoplasia development. Based on these concepts, the author has proposed a short-term (thirteen-week) assay for screening for carcinogenic potential based on a mode of action analysis and on readily available, identifiable preneoplastic changes. A screening assay that detects all potential rodent hepatocarcinogens has been previously identified (Toxicol Pathol 32 [2004], 393—401) including increased liver weight, hepatocellular necrosis, hypertrophy, and cytomegaly. Labeling index for DNA replication might supply additional support. These markers have high sensitivity but low specificity. However, most chemicals can be appropriately classified as to their mode(s) of action for hepatocarcinogenesis with follow-up mechanistic studies, and a rational evaluation of their relevance to humans can be made. A similar process can be envisioned for other tissues for evaluation for carcinogenic potential. [ABSTRACT FROM PUBLISHER]

The two-year cancer bioassay in rodents remains the primary testing strategy for in-life screening of compounds that might pose a potential cancer hazard. Yet experimental evidence shows that cancer is often secondary to a biological precursor effect, the mode of action is sometimes not relevant to humans, and key events leading to cancer in rodents from nongenotoxic agents usually occur well before tumorigenesis and at the same or lower doses than those producing tumors. The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) hypothesized that the signals of importance for human cancer hazard identification can be detected in shorter-term studies. Using the National Toxicology Program (NTP) database, a retrospective analysis was conducted on sixteen chemicals with liver, lung, or kidney tumors in two-year rodent cancer bioassays, and for which short-term data were also available. For nongenotoxic compounds, results showed that cellular changes indicative of a tumorigenic endpoint can be identified for many, but not all, of the chemicals producing tumors in two-year studies after thirteen weeks utilizing conventional endpoints. Additional endpoints are needed to identify some signals not detected with routine evaluation. This effort defined critical questions that should be explored to improve the predictivity of human carcinogenic risk. [ABSTRACT FROM PUBLISHER]

In carcinogenicity studies with PPAR g and α/γ agonists, urinary bladder tumors have been reported in Harlan Sprague-Dawley (HSD) and Charles River Sprague-Dawley (SD) but not Wistar (WI) rats, with urolithiasis purported to be the inciting event. In two 3-month studies, the authors investigated strain-related differences in urine composition by sampling urine multiple times daily. Urine pH, electrolytes, creatinine, protein, citrate and oxalate levels, and serum citrate were assessed; urine sediment was analyzed by scanning electron microscopy and energy dispersive x-ray spectroscopy. HSD rats had significantly higher urine calcium than SD or WI rats, primarily as calcium phosphate-containing precipitate. When compared to SD rats, HSD rats had lower urine volume, higher urine protein, and a comparable (week 4) to lower (week 13) burden of MgNH4PO4 aggregates. Relative to WI rats, HSD rats had higher urine protein and magnesium and lower serum and urine citrate. Overall, the susceptibility to urolithiasis in male rats was HSD > SD > WI; this was likely due to strain-related differences in the amount of urine protein (a nidus for crystal formation), lithogenic ions, citrate (an inhibitor of lithogenesis), and/or volume. Strain-related differences in urine composition need to be considered when interpreting the outcome of studies with compounds that alter urine composition. [ABSTRACT FROM AUTHOR]

Based on epidemiological data, chronic exposure to high levels of inorganic arsenic in the drinking water is carcinogenic to the urinary bladder of humans. Recently, models have been developed involving transplacental administration of inorganic arsenic and subsequent administration of another substance that produces a low incidence of urogenital neoplasms. Administration of arsenite or arsenate in the diet or drinking water to five-to eight-week-old mice or rats rapidly induces urothelial cytotoxicity and regenerative hyperplasia. In mice administered arsenite, we observed eosinophilic intracytoplasmic granules present in the urothelial cells. These granules were not present in urothelial cells of untreated mice or in treated or untreated rats. By transmission electron microscopy, the granules were located within the mitochondrial matrix, that is, mitochondrial inclusions. Arsenic, primarily as arsenite, was present in partially purified mitochondria containing these granules. Cells containing the granules were not usually associated with degenerative changes. Lack of these granules in rats suggests that they are not necessary for inorganic arsenic-induced urothelial cytotoxicity or hyperplasia. These granules have also been observed with exposures to other metals in other tissues and other species, suggesting that they represent a protective mechanism against metal-induced toxicity. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor gamma (PPARγ) and dual PPARα and γ agonists have been developed for use in the treatment of diabetes and hyperlipidemias. Vascular tumors were increased in mice treated with some PPAR agonists, but not in rats. Spontaneous hemangiosarcomas are common in several strains of mice, uncommon in rats, and rarely occur in humans. The objective of this study was to determine the endothelial cell proliferation rate in liver and adipose tissue of B6C3F1 mice, F344 rats, and humans to aid in investigations of the genesis and development of hemangiosarcoma formation, and to determine the relevance of the increased endothelial cell proliferation rate in drug-treated rodents in assessing the risk of these drugs in humans. We determined the endothelial cell labeling index (LI) in untreated mice, rats, and humans, in normal liver, brown fat (rats and mice only) and white fat by dual immunohistochemistry of CD31 and Ki-67. The LI, highest in mice and lowest in humans, was statistically significantly greater in the mouse compared to the human and rat. The increased rate of spontaneous or PPAR agonist-induced hemangiosarcoma formation in mice may be related to the higher background endothelial cell proliferation rate compared to rats and humans. [ABSTRACT FROM AUTHOR]

Examination of the urine and the bladder epithelium are essential to the investigation of mechanisms of urinary bladder carcinogens in rodents. However, urine and bladder tissue specimens must be collected and processed properly if accurate data are to be derived. The optimum specimen for analysis of urinary constituents is fresh void urine collected from nonfasting animals. Fasting the animal prior to urine collection changes the normal composition, including pH. Many of the normal urinary constituents can influence the mode of action of bladder carcinogens, especially for non-genotoxic agents. Light microscopy is routinely used to examine the bladder epithelium. However, it is often necessary to use more sensitive techniques, such as scanning electron microscopy (SEM) to detect subtle cytotoxic changes in the superficial cell layer of the urothelium, and bromodeoxyuridine (BrdU) incorporation, PCNA, or Ki-67 immunohistochemistry to determine the labeling index for cell proliferation. The urinary bladder must be handled gently and inflated with fixative in situ before the animal dies to avoid artifactual autolytic damage to the bladder epithelium that is visible by SEM and may be mistaken for treatment-related changes. The purpose of this paper is to provide information for the proper collection and examination of urine and the urinary bladder. [ABSTRACT FROM AUTHOR]

Muraglitazar, a PPARα/γ agonist, dose-dependently increased urinary bladder tumors in male Harlan Sprague–Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1% NH4Cl-acidified diet. Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed. In control and treated rats fed a normal diet, urine pH was generally &nvge; 6.5, which facilitates formation of calcium-and magnesium-containing solids, particularly in the presence of other prolithogenic changes in rat urine. Urinary citrate, an inhibitor of lithogenesis, and soluble calcium concentrations were dose dependently decreased in association with increased calcium phosphate precipitate, crystals and/or microcalculi; magnesium ammonium phosphate crystals and aggregates; and calcium oxalate-containing thin, rod-like crystals. Morphologically, sustained urothelial cytotoxicity and proliferation with a ventral bladder predilection were noted in treated rats by month 1 and urinary carcinomas with a similar distribution occurred by month 9. Urothelial apoptotic rates were unaffected by muraglitazar treatment or diet. In muraglitazar-treated rats fed an acidified diet, urine pH was invariably < 6.5, which inhibited formation of calcium-and magnesium-containing solids. Moreover, dietary acidification prevented the urothelial cytotoxic, proliferative, and tumorigenic responses. Collectively, these data support an indirect pharmacologic mode of urinary bladder tumor development involving alterations in urine composition that predispose to urolithiasis and associated decreases in urine-soluble calcium concentrations. [ABSTRACT FROM AUTHOR]

The sequencing of the human and mouse genomes, and soon that of the rat, offers a foundation to evaluate biological phenomena, including toxicologic effects. Numerous tools are being developed to evaluate aspects of biology based on the DNA sequence. These tools can be utilized to evaluate absorption, distribution, metabolism and excretion, and effects of the toxicologically active product on the target organ. The genes involved can be broadly categorized as those affecting susceptibility to a toxicologic effect and those that are involved in the biologic response. For risk assessment to be performed in a rational manner, fundamental mechanisms of toxicologic processes must be ascertained. Based on successes already achieved, such as development of transgenic and knockout mouse strains, the application of aspects of the genomics revolution could be useful in developing a better understanding of mechanisms, and possibly in identifying specific markers of responses. In addition, genomics are likely to be useful in translating effects between species. However, genomics are being portrayed as the ultimate solution to all of toxicology. This is hardly the case. Basic chemistry, biochemistry, toxicokinetics, pharmacology, and pathology will continue to be needed in the overall weight of evidence approach to risk assessment. Genomics are likely to be of limited usefulness in predicting individual, in contrast to population susceptibility to various toxicological responses. Concordance of various diseases in identical twins, for example, different cancers, is rarely greater than 20% over the lifetime of these individuals. Similarly, genomics are likely to be of limited usefulness in screening for toxicologic end points. As with other tools of biology, those to be developed based on the genome are likely to provide greater usefulness in dissecting the mechanistic processes involved and defining the basis for susceptibility. [ABSTRACT FROM AUTHOR]

Bladder neoplasia in humans consists of 2 diseases, a low-grade papillary tumor that does not invade or metastasize, and a high-grade lesion that usually invades and metastasizes. Bladder carcinogenesis in rats is most like the low-grade, papillary tumor, although it eventually does progress and invade. In the mouse, models are available that mimic each of these disease processes. Preneoplastic lesions in humans and rodents include various types of hyperplasia, proliferative cystitis, and dysplasia. These preneoplastic and neoplastic lesions arise throughout the urothelium, from the renal pelvis to the urethra, although most commonly in the bladder. Rarely, benign and malignant mesenchymal lesions occur in rats and mice, with a unique submucosal mesenchymal lesion present in some strains of mice. In addition, eosinophilic and clear inclusions in the superficial layer of urothelium in mice, which do not appear to be associated with toxicity or carcinogenesis, have been reported. An approach to evaluation of carcinogenic mechanisms involved in the urothelium is presented. It focuses on distinguishing between DNA reactive carcinogens vs those that act by increasing cell proliferation. Although rodent models do not precisely mimic the human disease, they have provided useful models for furthering our understanding of the carcinogenic process in the urothelium as it pertains to human diseases. [ABSTRACT FROM AUTHOR]

Few studies have examined the carcinogenicity of chemicals toward the urinary bladder in hamsters, and the effect of diet on hamster urine and urothelium has not been reported. Our laboratory recently began investigating the effects of dimethylarsinic acid (DMA) on the hamster bladder, and we noticed subtle urothelial changes even in controls. The possible effect of various diets on hamster urothelium was evaluated by feeding different diets to 4-week-old Syrian Golden hamsters for 5 weeks. The diets examined were Tekland 8656, Purina 5002, Purina 5L79, and NIH-07. Light microscopic examination showed a slight increase in urothelial hyperplasia in hamsters fed Purina 5L79. An increase in the incidence of urinary bladder necrosis, exfoliation, and mild hyperplasia were noted by scanning electron microscopy (SEM) with all dietary preparations except NIH-07. The constituents in the diets producing the urothelial alterations are not known at present, but NIH-07 diet was chosen for experiments to investigate the effects of DMA on the hamster bladder epithelium. Male and female 5-week-old Syrian Golden hamsters were fed 100 ppm DMA for 10 weeks. Examination of urinary parameters showed no treatment-related changes. Light microscopic examination and SEM revealed no changes of the urothelium of DMA-treated male or female hamsters. [ABSTRACT FROM AUTHOR]

Twenty-one chemicals were evaluated by standardized protocols in 6 mouse models that have been sugggested as alternatives to the 2-year mouse bioassay. Included were genotoxic and nongenotoxic chemicals, carcinogens and noncarcinogens, immunosuppressive and estrogenic agents, peroxisome proliferators, and chemicals producing cancer in rodents by other mechanisms. Mice were sacrificed at the end of 6 to 12 months, depending on the model. Standardized histopathology, biostatistical analyses, and criteria for overall evaluation of the results were employed. The TgAC transgenic (dermal and oral administration), the Tg-rasH2 transgenic, the heterozygous p53 gene knockout, the homozygous XPA and homozygous XPA–heterozygous p53 gene knockout, and the neonatal mouse models were evaluated. The chemicals were also evaluated in the in vitro SHE assay. Comparison of the results between the various in vivo models suggest that they might have usefulness as screening bioassays for hazard identification for potential human carcinogens. They have the benefits of being quicker, less expensive, and involve fewer animals than the traditional 2-year mouse bioassay. They do not appear to be overly sensitive. However, they do not definitively distinguish between genotoxic and nongenotoxic carcinogens, and they do not have 100% specificity for identifying human carcinogens. Like the 2-year bioassay, the results from these models need to be evaluated in conjunction with other information on a chemical in an overall weight-of-evidence, integrated analytical approach to assess risk for human exposures. [ABSTRACT FROM AUTHOR]

Sulfosulfuron, developed as a herbicide, caused increased microcrystalluria and the formation of urinary tract calculi when fed to male and female rats in a chronic 2-year study at doses of 5,000 ppm and 20,000 ppm. Hyperplasia was also seen in urinary bladders at 5,000 ppm and 20,000 ppm, almost exclusively in the presence of observable calculi/microcalculi. Urinary bladder tumors were found in 2 females in the 5000 ppm group, both in the presence of calculi. No increased microcrystalluria, calculi, or tumors were found at doses of 500 ppm and lower. In the current study, 5 groups of male Sprague–Dawley rats were fed sulfosulfuron at doses of 50, 500, 5,000, and 20,000 ppm for 10 weeks. Ten animals were co-administered 5,000 ppm sulfosulfuron with 12,300 ppm NH[sub 4]Cl to determine if inhibition of the formation of calculi would prevent any urothelial effects of treatment with sulfosulfuron. Ten animals in the control group and in the high-dose sulfosulfuron group were fed only basal diet for an additional 10 weeks to determine if the effects of sulfosulfuron on the bladder epithelium were reversible. There was an increased incidence of microcrystalluria observed at 5,000 and 20,000 ppm. There was no increase in microcrystalluria observed in the urine of rats co-administered sulfosulfuron and NH[sub 4]Cl. Urinary bladder calculi were found in the bladder of 1 animal fed 20,000 ppm. Examination by light microscopy showed diffuse papillary/nodular hyperplasia of the bladder epithelium in this animal. No increased microcrystalluria was observed after withdrawal of the chemical from the diet and the bladder epithelium was normal by light microscopy. The hyperplastic effects associated with the feeding of high doses of sulfosulfuron occur only with the appearance of urinary tract calculi. Based on these results and anatomical differences between rats and humans, it may be concluded that the hyperplastic and carcinogenic effects of sulfosulfuron in rats are high-dose, threshold phenomena that are not likely to occur in humans under environmentally relevant exposures. [ABSTRACT FROM AUTHOR]

A biological model of carcinogenesis has been developed that can be expressed mathematically, and therefore can be studied using computer-based analyses. It is based on several assumptions: Carcinogenesis occurs in two stages: initiation and transformation (to malignant tumors); the carcinogenic events can occur only in stem cells or their functional equivalents; these events can occur only during the active part of the cell cycle; each of the events occurs in a probabilistic fashion. Cell dynamics are thus an extremely important part of carcinogenesis. Any agent can have an impact on the carcinogenic process by either directly altering the genome (genotoxic) or increasing the proliferative rate of the tissues: increasing the number of cell divisions through which a spontaneous alteration in the genome can occur; or an agent can affect both of these. Effects on the genome and on cell proliferation can have different dose-responses. Extrapolation to low doses requires consideration of the dose-response for each effect. Differences in mechanisms affecting cell proliferation and genetic changes need to be considered in determining thresholds.The model was originally validated utilizing tumor incidence data from multiple experiments with the carcinogen, N-[4-(5-nitro-2-furyl)2-thiazolyl]-formamide (FANFT), in rats. FANFT is a strong mutagen, is metabolically activated to a reactive electrophile, binds to DNA, and also increases cell proliferation. Modeling analyses demonstrate that the tumor dose-response curve for FANFT can be explained based on a combination of the individual dose-response of its genotoxic and cell proliferation effects.Modeling of a nongenotoxic compound, sodium saccharin (Na S), has also been evaluated. It is not metabolized to a reactive electrophile (it is actually nucleophilic), does not bind to DNA, and is not mutagenic. Nevertheless, in two-generation experiments at high doses it induces a significant incidence of bladder tumors in male rats. It is also a strong tumor-promoting substance following chemical initiation or bladder ulceration. These complex protocols can be readily explained by the proliferative response induced in the urothelium following Na S administration. As expected for a nongenotoxic chemical, there is no effect on the probability of initiation or transformation. Unlike the sodium salt, high doses of the calcium and acid forms of saccharin do not increase cell proliferation significantly, and would not be anticipated to induce tumors. Also, there appears to be a threshold effect related to dose of Na S and the induction of urothelial proliferation. Since cell proliferation is the mechanism by which Na S induces bladder tumors in rats, it is expected that there is also a threshold with respect to carcinogenesis.By allowing for agents to be defined in terms of their ability to affect the genome directly or to act as cell proliferators, model-based analyses provide a rational basis for extrapolating from high doses in animal experiments to low doses in assessing risk for humans. [ABSTRACT FROM PUBLISHER]

In almost half the patients seeking advice for anxiety, panic and phobias the cause was alcohol or benzodiazepines. In the remainder it was psychological, usually a state of conflict or a traumatic event. When symptoms are persistent following a distressing event it is often the case that alcohol or benzodiazepines are keeping them going. There is a large variation in individual vulnerability and the mechanism responsible for these symptoms is rebound arousal. [ABSTRACT FROM AUTHOR]

Concha bullosa, a pneumatized middle turbinate, is a common anatomic variant found in the paranasal sinuses. When a concha bullosa becomes obstructed, it can form a mucocele and, eventually, a mucopyocele if it becomes secondarily infected. This is a rare phenomenon; only 9 concha bullosa mucopyoceles have been previously reported in the English-language literature. We present the case of a large concha bullosa mucopyocele in a pediatric patient in which the concha bullosa replaced the anterior ethmoid sinuses and was contiguous with the frontal sinus. [ABSTRACT FROM AUTHOR]

The article presents an obituary for Doctor Nobuyuki Ito.

Reports on a case of peripheral gangrene associated with dopamine infusion in a child. Physical findings; Clinical management.

Addresses comments to a study about Syrian hamster embryo assays. Importance in developing screening tools for rodent carcinogens; Purpose of assays; Way in which the assay is used.

A letter to the editor is presented in response to an article regarding medical care in the April 1998 issue.