Mesenchymal proliferation with decidual-like morphology in seminal vesicles of aging mice.

Lesions characterized by spindle and epithelioid cells and nuclear progesterone receptors are described in seminal vesicles of four aging mice. The lesions of two mice also contain granular metrial gland (GMG)-like cells. The same cellular details are seen in the uterine decidual reaction and the similar urinary bladder lesion in mice, also called mesenchymal tumor. Therefore, it is hypothesized that these lesions in male accessory sex glands and the urinary bladders of aging male and female mice are of mesenchymal origin with the potential for differentiation along several pathways, leading especially to lesions with decidual-like morphology, but also to lesions which contain only spindle cells. The decidual hypothesis is further supported by the occurrence of round eosinophilic granules and focal necrosis, interpreted as a sign of regression in all these lesion types. The bilateral lesions of a fifth mouse consist of spindle cells and scar-like tissue, the latter suggesting regression, and lack epithelioid and GMG-like cells. In this case, verification of the diagnosis depends on the demonstration of progesterone receptors, absent in normal glands. Uterine decidual reactions during pregnancy are brought about by priming with progesterone/estrogen, initiation through the blastocyst, and maintenance through progesterone. Experiments by others show that priming may also occur through growth factors/growth hormone, initiation through prostaglandins, and maintenance through testosterone in mice. It is hypothesized that upon such stimulation, certain cells in male accessory sex glands and the urinary bladder, possibly derived from the Muellerian ducts or other subperitoneal tissue, appear to have the potential in mice of developing into spindle and epithelioid cells, including decidual-like cells. All published uterine decidual reactions and lesions with decidual-like morphology in other organs of mice stayed within the peritoneal coverage of their respective organ and did not metastasize despite their "anaplastic", tumor-like appearance. Thus, they should be considered non-neoplastic. It is proposed to name above lesions in male accessory sex glands and urinary bladders "mesenchymal proliferation, decidual type" or "mesenchymal proliferation, spindle-cell type", depending on their cellular characteristics.

The genetic epidemiology of schizophrenia and of schizophrenia spectrum disorders.

It has been known for a long time that schizophrenia and several related psychopathological traits aggregate in families on a common genetic basis. Improved methodology of recent family, twin and adoption studies has led to a better unterstanding of which psychopathologically defined syndromes and personality traits are part of a schizophrenia spectrum, and to which degree individual spectrum conditions share the same genetic background with schizophrenia. The spectrum concept has been extended to include neuropsychologically, neurophysiologically and neuroradiologically measurable familial traits as subclinical endophenotypes of schizophrenia that may be more fundamental to the development of the disease than overt psychopathology. This knowledge has been useful in designing molecular genetic linkage and association studies that aim at directly identifying individual risk genes. Replicable linkage findings have emerged from genome scans that imply at least seven chromosomal regions to harbour schizophrenia susceptibility genes. They strengthen the conviction that schizophrenia is indeed a genetically complex disorder, based on a larger number of susceptibility genes with risk-increasing alleles that are common in the population and exert a limited effect on the individual level. Although demanding increased investments into sample collection, genotyping and computational technology, identification of these genetic variants will be possible and worthwhile since they may have a large effect in terms of population attributable risk.

"Mesenchymal tumor" or "decidual-like reaction"?

For more than 40 yr, an unusual urinary bladder lesion has been known to occur in certain strains of mice, but no consensus has been obtained regarding its etiology, pathogenesis, biology, or classification. The lesion was first assumed to be epithelial and non-neoplastic, then it was called a smooth muscle cell tumor or leiomyosarcoma because of ultrastructural characteristics for smooth muscle cells. Later, the nonspecific term "mesenchymal tumor" was introduced due to histomorphologic differences from all smooth muscle tumors known. Recently, a proposal was made to name it "decidual-like reaction" because of the histomorphologic similarity to the rare spontaneous decidual reaction in the uterus of aging mice. Both lesions are characterized by spindle and large pleomorphic epithelioid cells with large bizarre nuclei; these characteristics mimic anaplasia of malignant tumors and led pathologists to assume a neoplastic nature. The decidual hypothesis is supported by the regular presence of nuclear progesterone receptors, the occasional occurrence of eosinophilic cytoplasmic granules, the rare finding of cells morphologically resembling granulated metrial gland cells (all also observed in the uterine decidual reaction), and the reproducibility through long-term feeding of combinations of estrogens and progestogens. It appears that the new decidual hypothesis can explain many detailed facets of the lesion, with the exception of the reported smooth muscle cell characteristics. The controversy of "mesenchymal tumor versus decidual-like reaction" should be resolved soon, not only as a scientific issue, but also because of consequences for risk assessment.

Similarities between the uterine decidual reaction and the "mesenchymal lesion" of the urinary bladder in aging mice.

The histopathologic characteristics of the decidual reaction in the uterus of aging mice and the "mesenchymal lesion/tumor" in the urinary bladder of aging mice are compared and found to be very similar. Both lesions consist of spindle and epithelioid cells, may contain round eosinophilic granules and possess nuclear progesterone receptors and cytoplasmic desmin. The decidual reaction derives from endometrial stromal cells, while the "mesenchymal lesion" apparently develops from mesenchymal cells near the trigone area, carrying or developing progesterone receptors. If the hypothesis is accepted that in aging mice the uterine decidual reaction and the "mesenchymal lesion" in the urinary bladder represent an equivalent type of tissue reaction, then it follows that the typical "mesenchymal lesion" is not a tumor and could be called more specifically "decidual-like reaction".

Subacute oral toxicity of tetraethylene glycol and ethylene glycol administered to Wistar rats.

A subacute toxicity study with administration of tetraethylene glycol in dosages of 0-220-660-2000 mg/kg body weight to male and female Wistar rats via gavage was conducted in order to characterize a possible toxic action of this compound. The structurally related compound ethylene glycol is known to cause kidney toxicity. Therefore, special attention was paid to investigating possible toxic effects of tetraethylene glycol on this organ. In order to compare possible treatment-related effects of tetraethylene glycol with those known from ethylene glycol, a group of male and female rats was treated with 2000 mg ethylene glycol/kg body weight. Daily oral application of tetraethylene glycol over 4 weeks was tolerated without toxic effects up to and including 2000 mg/kg body weight. Daily oral application of ethylene glycol over 4 weeks resulted in treatment-related effects on the kidneys. A slight decrease in the urinary excretion of potassium, calcium and phosphate (males), a diminished pH-value of the urine, and a slight increase in osmolality (females) were observed. In both sexes excretion of oxalate was significantly increased and microscopic examination of urinary sediment revealed calcium oxalate crystals. Kidney weights of males and females were slightly elevated. Histopathology revealed crystals in renal tubuli, renal pelvis, and urinary bladder; tubulopathy and epithelial hyperplasia within the renal pelvis were also observed. Therefore, the study confirmed the kidney as target for ethylene glycol toxicity and gave no indications of tetraethylene glycol-induced toxic effects.

Calcium channel blockers and the risk of cancer: a preclinical assessment.

The preclinical evidence for a potential influence of calcium channel blockers (CCBs) on carcinogenesis is discussed in the light of a broad database from rodent carcinogenicity studies as well as literature data. In all bioassays performed in rats and mice on the dihydropyridine CCBs--nifedipine, nimodipine, nisoldipine, and nitrendipine--no evidence was found for a carcinogenic potential of these compounds. Calcium is an essential intracellular signal for cell proliferation and apoptosis. The crucial role of increased cell proliferation in all stages of carcinogenesis is well documented. Some indirect experimental evidence also points to a role of defective apoptosis in tumor promotion. CCBs uniformly inhibit cell proliferation, whereas the influence of CCBs on apoptosis is inconsistent, resulting in an inhibition or increase in apoptosis dependent on cell type. Accordingly, antitumorigenic effects of CCBs have been reported based on their antiproliferative action. A tumor-promoting effect of CCBs based on inhibition of apoptosis, however, remains purely speculative and, in fact, can be denied based on the results of in vivo bioassays. It is therefore concluded that there is no preclinical evidence that should give rise to concern over the carcinogenic potential of dihydropyridine-type CCBs.

Risk assessment of carcinogens in food with special consideration of non-genotoxic carcinogens. Scientific arguments for use of risk assessment and for changing the Delaney Clause specifically.

The document "Risk Assessment of Carcinogens in Food with Special Consideration of Non-Genotoxic Carcinogens" was produced by the International Federation of Societies of Toxicologic Pathologists on the occasion of its triannual meeting in Tours, France, April 23-26, 1995. Subsequently, it was endorsed by the North American Society of Toxicologic Pathologists at its annual meeting in San Diego, CA, USA, June 11-15, 1995. This document was written to address up-to-date risk assessment of carcinogens and anachronisms in the Delaney Clause of the US Federal Food, Drug and Cosmetic Act which have become evident since its enactment in 1958. In the intervening years, major progress has been made in understanding mechanisms of cancer induction and in recognizing causes of human cancer. The Clause in conjunction with its present legal interpretation and implementation does not provide for rational, scientific evaluation of carcinogens. It ignores the fact that the diverse mechanisms now known to underlie cancer increases in rodents exposed to high doses of chemicals are often inapplicable to man. In this regard, current evaluation of chemicals based on the tenets of the Delaney Clause is irrational in many cases. The document presents several examples of chemicals to which humans may be exposed through food and which illustrate the need for science-based risk assessment. Appropriate risk assessment methods are available to provide assurance of negligible risk, and accordingly, it is recommended that the Delaney Clause be rescinded as it has outlived its usefulness. This will enable US governmental agencies to regulate the use of chemicals in foods by using appropriate current scientific methods on a case by case basis within the context of other relevant legislation.

RITA--registry of industrial toxicology animal-data--guides for organ sampling and trimming procedures in rats.

RITA (Registry of Industrial Toxicology Animal-data) is a pathology data base for the collection of validated histopathological data on tumours and potentially pre-neoplastic lesions observed in laboratory rodents. To enable a better comparison of information, standardized techniques for the preparation of histological slides have been established for all organs. The current paper describes the guidelines for organ sampling and trimming procedures applied in the RITA project, i.e. the number of sections to be taken, the direction in which an organ should be cut, the localization (anatomical site) from which a sample should be taken, and the size of an organ (or part of an organ) to be placed in cassettes for processing. Schematical illustrations and additional explanations are provided to support the proposed standardized procedures in histology laboratories.

Aberrant craniopharyngeal structures within the neurohypophysis of rats.

Aberrant craniopharyngeal structures within the neurohypophysis were analyzed in 17 rats, originating from four different colonies of Sprague-Dawley- and Wistar-derived strains, which were used for toxicity studies in five different laboratories. Males were more frequently affected than females. The incidence of these findings, which occurred spontaneously and mainly in aged rats, was very low. Predominant features included tubular or acinar glandular structures, rarely embedded in a fibrous stroma, and, as a rule, not compressing adjacent tissue. In some cases, large cysts filled with colloid-like, amorphous material and cellular debris were present. The tubular structures consisted of a rather flat epithelium, while the cystic elements were lined by a cuboidal or columnar, rarely ciliated epithelium, containing goblet cells, or by a stratified squamous epithelium. These structures reacted positively for cytokeratin. Acinar structures mimicked salivary glands of the serous or mucinous type. In a few cases, small, round or fusiform cells were present. Distribution and predominance of the various epithelial structures depended on the strain and colony of rats. Considering the ontogenic development of the pituitary gland, the morphological aspect of these lesions, their immunoreactivity and former reports on similar findings, we concluded that these rats have aberrant craniopharyngeal structures within the pars nervosa of the hypophysis, originating from remnants of the oro-pharyngeal epithelium of the craniopharyngeal duct (RATHKE's pouch). These lesions, which occurred in different strains and colonies of laboratory rats, represent heterotopias or choristomas, consisting of non-neoplastic growth disturbances. Being of a distinctly non-proliferative nature, they should not be confused with craniopharyngiomas.

Osteochondroma in laboratory rats: a report of 3 cases in a Fischer-344, a Sprague-Dawley, and a Wistar rat.

Three cases of osteochondroma in a male Sprague-Dawley (SD) rat, a female Fischer (F344) rat, and a male Wistar rat are described. The rats were aged between 26 and 30 months. All osteochondromas were considered to be of spontaneous origin. The Wistar rat had multiple osteochondromas on both hind legs, the skull base, and a lumbar vertebra, whereas each of the F344 and SD rats was affected by a solitary osteochondroma, also on a lumbar vertebra. The lumbar osteochondromas were similar in appearance in all rats and consisted of a central core of trabecular bone, interspersed with fatty marrow and covered by a cap of hyaline cartilage. The additional tumors in the Wistar rat represented different developmental stages of osteochondroma with or without endochondral activity. The osteochondromas in the rats were morphologically similar to those described in humans and some domestic animal species.

Spontaneous tumors of 2000 Wistar TNO/W.70 rats in two-year carcinogenicity studies.

Eleven two-year toxicity/carcinogenicity experiments in control Wistar TNO/W.70 rats were started between 1973 and 1976. Tumors occurring were compiled on the basis of histopathological reports. Of the 1,000 male and 1,000 female rats at the beginning of the studies, 962 males and 968 females were evaluated. The remaining animals were unavailable due to autolysis or early death (before day 400). The histopathologic diagnosis for the eleven reports were performed by five different pathologists or groups of pathologists. A total of 827 tumors (375 in males and 452 in females) was seen in 686 rats (303 males, 383 females). 183 tumors (67 in males, 116 in females) were classified as malignant. 719 (86.9%) of all tumors and 120 (65.6%) of all malignant tumors were located in endocrine organs (pituitary, thyroid, adrenal, pancreatic islets) or in genital organs (testes, epididymides, seminal vesicles, ovaries, uterus, mammary gland). Average incidences of primary tumors found in the following organs were: pituitary 20.0%, thyroid 9.6%, uterus 9.2%, adrenals 4.1%, mamma 3.2%, testes 2.9%, ovaries 1.8%, skin 1.4% and 17 other organs each with a tumor frequency below 1%. This wide spectrum of spontaneous tumors with a mostly low incidence makes the Wistar rat a preferred strain for carcinogenicity studies. Despite nearly identical husbandry conditions, a marked variability was observed among experiments regarding the general incidence of benign and/or malignant tumors, particular tumors, and number of tumor-bearing animals. Differences in mortality among experiments had no pronounced effect on the variability of tumor incidences. Different evaluation criteria used by different pathologists did not appear to be a major cause of the observed variability with the probable exception of lesions in endocrine organs. The major cause would seem to be the biological variability of the animal material. The observed marked variability of tumor incidences between experiments would indicate that a considerable natural variability may also occur between groups of one carcinogenicity study. Therefore, information on historical control tumor data from the same rat strain kept under similar conditions is needed to interpret the incidences of tumors in carcinogenicity experiments.

Ovine abortion and stillbirth due to purulent placentitis caused by Yersinia pseudotuberculosis.

Yersinia pseudotuberculosis was isolated from an aborted placenta and stillborn lamb from a sheep flock having multiple abortions. Given intravenously, it caused elevated body temperatures and purulent placentitis in eight of nine ewes. Two ewes died following infection at 2.5 months of gestation. Two ewes infected at 3.5 months gestation aborted; three infected at four months gave birth to weak, premature, or moribund lambs. One ewe infected at 4.5 months gave birth to a healthy lamb. One lamb which died minutes after birth had focal necrotizing hepatitis, a lesion observed in a stillborn lamb during the original disease outbreak. Y. pseudotuberculosis was reisolated from endometrial, placental, and fetal lesions of experimentally infected animals.

In vitro phagocytic activity of neutrophils of various cattle breeds with and without Trypanosoma congolense infection.

A simple in vitro-technique using latex beads was used for the investigation of the phagocytic activity of neutrophils in bovines of different breeds, infected and non-infected with T. congolense. It was found that the N'Dama, assumed to be trypanotolerant, have a significantly higher number of neutrophils and neutrophils with phagocytic activity per mm3 blood, compared to the more susceptible Zebu, the Baoulé and the crossbreed M75, ranging between these two breeds. The first appearance of T. congolense in the blood was accompanied by a significant increase of phagocytizing neutrophils in 21 bulls of different breeds and 12 N'Dama cows in comparison to the pre-infection levels or to the animals which remained free of trypanosomes. A possible involvement of the neutrophils in the defence against trypanosomes by phagocytosis is discussed.

Curative effect of alpha-difluoromethylornithine on fatal Trypanosoma congolense infection in mice.

The curative effect of alpha-difluoromethylornithine (DFMO) on fatal T. congolense infection in mice was investigated using various concentrations administered orally in drinking water. Permanent cure was achieved in mice receiving 4% for 3 days or 2% for 5 days. Mice receiving less became parasitemic again but then, without any further treatment, resisted death due to trypanosomes for an average of 34.5 days, while untreated controls were dead within 8 days after trypanosomes were first seen in their blood.