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The Han: SPRD Pkd rat mutant is an autosomal dominant rat model with incomplete penetration of polycystic renal transformation. Progressive renal failure occurs in heterozygous male animals. The mechanisms of progression have not been elucidated. To identify some pathogenetic factors involved we subjected male SPRD Pkd rats (and their non-affected littermates as controls) to uninephrectomy (UNX), castration or enalapril treatment. To assess progression S-urea at age 150 days was chosen as endpoint. (i) In uninephrectomized male Han: SPRD Pkd (=12 animals per group) S-urea at age 150 days was consistently above 300 mg/dl, while it was 245 mg/dl (191–290) in control Han: SPRD Pkd. (ii) In castrated male Han: SPRD median S urea at 150 days was 100 mg/dl (69–211) compared to sham-operated male Han: SPRD controls (245; 191–290). Castration did not, however, prevent accelerated progression after uninephrectomy. (iii) Enalapril (50 mg/l) in the drinking fluid did not significantly lower median systolic blood pressure (by plethysmography) in animals on 0.2% sodium diet (at 185 days 160 mmHg; 140–170 versus 170; 140–195 in non-enalapril controls), although circulating ACE was significantly inhibited (17 U; 11–33 versus 89; 52–108 in controls). S-urea at age 185 days was not significantly different in the 2 groups. In conclusion, the Han: SPRD Pkd model differs from human ADPKD to some extent. Uninephrectomy accelerates renal failure in the rat, but not in humans. On the other hand, in contrast to human ADPKD the renin system is suppressed in the rat model and ACE inhibition does not affect the course of renal failure. [ABSTRACT FROM PUBLISHER]

During 1997-2008 two long-term (I and II) and two life-long (III and IV) experiments were performed analyzing the effect of chronic exposure to a low-intensity GSM-like signal (900 MHz pulsed with 217 Hz, 100 µW/cm² average power flux density, 38-80 mW/kg mean specific absorption rate for whole body) on health and survival of unrestrained female Sprague-Dawley rats kept under identical conditions. Radiofrequency (RF)-exposure was started at 52-70 days of age and continued for 24 (I), 17 (II) and up to 36 and 37 months, respectively (III/IV). In the first two experiments (1997-2000) 12 exposed and 12 sham-exposed animals each were observed until they were maximally 770 or 580 days old. In experiment I no adverse health effects of chronic RF-exposure were detectable, neither by macroscopic nor detailed microscopic pathological examinations. Also in experiment II no apparent macroscopic pathological changes due to treatment were apparent. Median survival time could not be estimated since in none of the groups more than 50% of the animals had died. In the course of two complete survival experiments (2002-2005; 2005-2008) 30 RF- and 30 sham-exposed animals each were followed up until their natural end or when they became moribund and had to be euthanized. A synoptical data analysis was performed. Survival data of all four groups could be fitted well by the Weibull distribution. According to this analysis median survival was significantly shortened under RF-exposure in both experiments by 9.06% (95% CI 2.7 to 15.0%) (p=0.0064); i.e by 72 days in experiment III and 77 days in experiment IV as compared to the corresponding sham-treated animals (III: 799 days; IV: 852 days). Both groups of animals of experiment III showed reduced median survival times by 6.25% (95% CI -0.3 to 12.4%) (p=0.0604) compared to the corresponding groups of experiment IV (53 days: sham-exposed animals, 48 days: RF-exposed animals) which may be due to the fact that animals of experiment III were born in October and animals of experiment IV in May indicating that the month of birth affects life span. From the results of the last two experiments it has to be concluded that chronic exposure to a low-intensity GSM-like signal may exert negative health effects and shorten survival if treatment is applied sufficiently long and the observational period covers the full life span of the animals concerned. The current data show that survival of rats kept under controlled laboratory conditions varies within certain limits depending on the month of birth. In view of our previous observations regarding an inhibitory or no effect of RF-exposure on DMBA-induced mammary cancer during the 1997-2000 period, an additional modulatory influence on a year-to-year basis should be considered which might be related to changing solar activity during the the 11-years' sunspot cycle. These potentially complex influences of the natural environment modulating the effects of anthropogenic RF-signals on health and survival require a systematic continuation of such experiments throughout solar cycle 24 which started in 2009.

The effect of development and growth of malignant tumors on pineal melatonin production was studied in two different hormone-dependent tumor systems in female rats. Urinary excretion of 6-sulphatoxymelatonin (aMT6s), the metabolic end product of melatonin, which parallels its production, was determined by radioimmunoassay at fortnightly or monthly intervals over the period of 1 year in female F344 Fischer rats bearing chemically-induced mammary carcinomas and in BDII/Han rats with spontaneous endometrial carcinomas. Untreated Fischer rats and BDII/Han rats in which tumor growth was suppressed by treatment with a progestin served as controls. Based on the cosinor analysis, animals without tumors showed significant seasonal rhythms of aMT6s excretion, with peaks in August (Fischer rats) and in May (BDII/Han rats). In contrast, such rhythms were absent in animals with developing and manifest tumors. It is concluded that animals kept under constant environmental conditions still show seasonal rhythms of pineal activity. Tumor development and growth affect pineal activity leading to disturbance of these rhythms.

Female virgin BDII/Han rats develop spontaneous endometrial carcinoma (EC) in incidences up to 90%. Our objective was to determine whether lifelong administration of the progestin melengestrol acetate (MGA) would suppress those tumors. Four groups of 20 rats aged 24-28 days were employed Group I animals were untreated controls. Groups II, III, and IV were fed 0.1, 0.2, and 0.4 mg MGA/kg daily in their diet during their lifetimes. All treated groups were free from EC during their lifetimes with an increased lifespan up to 30%. The controls, in contrast, had an EC incidence of 85%. Histologically, with one exception all tumors were classified as adenocarcinoma. While most of the control rats died from EC, nearly all animals of groups II and III died from age-related diseases. Rats in group IV showed side effects due to the glucocorticoid properties of MGA. Besides alopecia and obesity an acceleration of chronic progressive nephrosis was observed. The study establishes the validity of the prophylactic approach to spontaneous hormone-dependent cancers in a rat tumor model.

Although Lewis rats are frequently used in biomedical research, little is known about their life-data and spontaneous pathology. Therefore, it was the aim of this study to determine the life expectancy, spectrum and incidence of spontaneous neoplasms of the inbred rat strain LEW/Han. A total of 629 LEW/Han rats (305 females and 324 males) from a specified pathogen-free breeding colony were kept from weaning up to their natural death under defined environmental conditions. A complete histological examination was performed on all organs and macroscopically altered tissues of all animals which died during the first three years of the study. These were 296 female (98%) and 213 male (66%) rats. The mean lifespan of the females (27.7 +/- 5.1 months) was significantly shorter than that of the males (32.5 +/- 6.6 months). In both sexes, the lifespan was mainly determined by the occurrence of neoplasms. Of the large spectrum of 52 histologically different tumour types, the highest incidences were observed for adenomas of the pituitary gland and adenomas/adenocarcinomas of the adrenal cortex in both sexes, mammary gland tumours and endometrial carcinomas in females, and C-cell adenomas/adenocarcinomas of the thyroid gland and tumours of the haemopoietic system in males. Of these, the high incidences of tumours of the haemopoietic system in males (27.7%) and of endometrial carcinomas in females (45.2%) should be considered as characteristic features of the strain.

A report is given on the history and pathology of an enzootic outbreak of spontaneous Pneumocystis carinii pneumonia (PCP) that occurred in a colony of male and female athymic Han:RNU rnu/rnu and Han:NZNU rnuN/rnuN rats maintained in a longevity study from weaning up to their natural death. The rats were obtained from specified pathogen free (SPF) breeding colonies and were kept in a barrier type animal quarter with standardized housing conditions. Groups of heterozygous, euthymic littermates in the same room remained unaffected. First cases of PCP were observed simultaneously in both stocks and both sexes when the rats were 15 to 18 months old. During the following 18 months, most of the animals developed pneumonia. Shortly prior to death the animals showed dyspnea and cachexia. Gross examination revealed focal or diffuse pulmonary consolidation. Histologically, characteristic lung lesions consisted of an interstitial pneumonia with perivascular and peribronchiolar infiltrations and with clusters of foamy macrophages within single or groups of alveoli. Most prominent in moderate and severe infections was an amorphous, honey-combed eosinophilic material within enlarged alveolar spaces. The diagnosis was based on the histological identification of Pneumocystis carinii (Pc) cysts in lung sections stained with Grocott's methenamine silver and was confirmed immunohistochemically. The evaluation of all evidence leads to the conclusion that Pc was introduced into the experimental colony by care-takers. The high incidence of PCP and its resemblance to human PCP indicate the suitability of athymic Han:RNU and Han:NZNU rats as natural models for this disease.

A high percentage of endometrial carcinomas contain oestrogen and progesterone receptors. For endocrine therapy of recurrent endometrial carcinoma, only high-dose progestins are in clinical use. As, therefore, the development of new endocrine treatment strategies is of great interest, suitable animal models for this tumour are essential. Up to now, only human tumour xenografts transplanted in immune-deficient nude mice, but no syngeneic in vivo tumour models, have been available. In the present article we describe the hormone sensitivity of the EnDA endometrial adenocarcinoma of the DA/Han rat growing as s.c. implants in DA/Han rats and athymic nude mice in serial passage. In both species, the tumour expresses oestrogen, but no progesterone receptors. Transplanted in DA/Han rats or nude mice, ovariectomy reduced tumour weight by 64% and 46% respectively. In both species substitution of ovariectomized animals with oestradiol restored tumour weights to intact control levels. Oestradiol substitution of intact animals did not further enhance tumour growth. The growth of the primary tumour was inhibited by medroxyprogesterone acetate (MPA) at a dose of 100 mg/kg by 67% and by tamoxifen at a dose of 20 mg/kg by 38%. Lung metastases were regularly seen in both species, although to a lesser extent in nude mice than in DA/Han rats. Tamoxifen treatment did not alter the number of lung metastases, whereas MPA or ovariectomy produced a significant reduction in the number of lung metastases. The EnDA endometrial carcinoma of the DA/Han rat with respect to its oestrogen sensitivity, oestrogen receptor expression, morphology and metastatic growth, grossly resembles a typical endometrial adenocarcinoma and can therefore be regarded as a useful in vivo experimental model for the evaluation of new endocrine treatment strategies.

Inbred rats of the DA/Han and BDII/Han strains have been proposed as suitable model systems for studying hormonal carcinogenesis, because they die mainly from hormone-dependent endometrial adenocarcinoma. Here we characterize the RUCA-I cell line derived from an endometrial adenocarcinoma of an inbred DA/Han rat and the RUCA-II cell line derived from an endometrial adenocarcinoma of an inbred BDII/Han rat. The RUCA-I cell line, if transplanted to the neck of female DA/Han rats, gives rise to endometrial adenocarcinomas at the ectopic site. The morphology of these ectopically grown tumors is predominantly of the moderately differentiated sub-class. In contrast, ectopic tumor growth of the RUCA-II cell line can be observed only if cells are transplanted to athymic nude mice. Biochemically, both cell lines are characterized by the stable expression of estrogen receptors. However, no statistically significant mitotic response of RUCA-I and RUCA-II cells to estradiol was measurable, and no induction of expression of the progesterone receptor by estradiol was detectable, although estradiol transformed the estrogen receptor into its stable DNA-binding state. In contrast, the rate of proliferation of RUCA-I but not of RUCA-II cells was reduced in the presence of 10(-6) M tamoxifen. From these results we conclude that (i) both cell lines, RUCA-I and RUCA-II, represent a new and promising endometrial tumor model; (ii) the mechanism of the hormone-dependent growth regulation of RUCA-I and RUCA-II cells is obviously impaired; (iii) the RUCA-I cell line appears to be a suitable model system for the study of molecular aspects of estrogen- and tamoxifen-dependent gene expression.

The BDII/Han rat develops spontaneous endometrial adenocarcinoma, which appears virtually identical histologically to human endometrial adenocarcinoma. The incidence rate of cancer formation in the rat is 90% and the mean lifetime of the animals is 22 months. This animal model therefore, is useful in the study of molecular aspects of spontaneous transformation as well as mammalian neoplastic progression. In this study we address the in-situ expression of tenascin, an extracellular matrix glycoprotein, during normal cyclic growth, during development of proliferative states, and during malignant transformation of the endometrium. Trace amounts of immunocytochemically detectable tenascin were found in 10% of young BDII/Han rats with a normal estrus cycle. In these inbred animals no tenascin was detectable in uteri without neoplastic progressive alterations of the endometrium. Tenascin immunoreactivity first appeared during proliferation in one of three uteri with cystic glandular hyperplasia. Prominent tenascin expression was detectable in all adenomatous hyperplasia, but restricted to the stromal mesenchyme, that surrounded the glands. In all endometrial adenocarcinomas tested, essentially the entire extracellular space of the stromal mesenchyme was immunoreactive with anti-tenascin antibodies while the epithelial glands themselves were negative. This staining pattern was observed independent of the degree of tumor differentiation or extent of myometrial invasion. The tenascin staining pattern was not significantly altered in tumors transplanted into the soft tissues of the neck of female BDII/Han rats. From our studies we conclude that tenascin may be a marker for the early detection of proliferative endometrial states.(ABSTRACT TRUNCATED AT 250 WORDS)

Cushing's disease and Cushing's syndrome-like lesions were observed in four male rats. 2 revealed ACTH-positive pituitary tumours associated with bilateral adrenal cortical hyperplasia (case 1, 2). The other 2 rats had metastasizing adrenal cortical carcinomas with marked adrenal cortical atrophy of the opposite adrenal glands (case 3, 4). Pathological lesions observed varied between the animals and included "potbelly", severe obesity, fatty degeneration of the liver, atrophy of the pancreas and greater sublingual glands with fatty infiltration, testicular atrophy, ulcers of the forestomach and purulent inflammation in different organs.

In a longevity study a total of 394 Han:SPRD rats (200 males and 194 females) were kept in a barrier type animal quarter from weaning until their natural death. The mean life span of males was 29.6 +/- 5 months, that of females 27.6 +/- 6.2 months. The most frequent neoplasms in females were mammary gland tumours (63.4%). Neoplasms of endocrine organs were common in animals of both sexes. Thyroid neoplasms, predominantly of C-cell origin, occurred in 60% of the males and 51.5% of the females. Pituitary gland tumours were observed in 53% of male and 45.1% of female rats. Further frequent tumours of the endocrine system included phaeochromocytomas (23% in males, 15.5% in females), adrenal cortex neoplasms (6% in males, 13.5% in females) and tumours of islet cells of the pancreas (20.8% in males, 8.2% in females). An uncommonly high incidence of squamous cell neoplasms (16% in males; 9.3% in females) of the preputial and clitoral gland was observed in this stock. Further organs frequently affected by neoplasms were the skin/subcutis and brain.

Hereditary polycystic kidney disease (PKD) was observed in a Han:SPRD rat mutant. Cysts were of tubular origin and occurrence was more pronounced in males than in females. In male rats polycystic kidney disease was associated with a marked elevation of systolic blood pressure. Therefore this rat mutant can be considered as a laboratory animal model for renal hypertension associated with adult polycystic kidney disease in man.

Food consumption, development of body weight, lifespan and incidence of spontaneous diseases and tumours were investigated in 3 groups of 96 male Han:SPRD rats each maintained in a longevity study from weaning up to their natural death. All rats were fed a commercial cereal-based diet. One group received food ad libitum and was used as control group. Access to the diet was controlled in the other two groups by means of an automatic timer. The rats of one of the latter groups were fed nocturnally (4 x 42 min daily during the dark period) and those of the other adiurnally (4 x 42 min daily, each two times during dark and light period). Time-scheduled feeding caused an evident food restriction compared with the food consumption of the rats fed ad libitum. This food restriction, however, was significantly more pronounced in the younger animals during the first weeks after weaning than in the older rats. The body weight development corresponded to the feed intake. In animals subjected to food restriction the weight remained below that of rats fed ad libitum during all age periods. Furthermore, time-scheduled feeding caused an important increase of the mean life expectancy and a reduction in the incidences of chronic nephropathy and purulent and chronic forms of prostatitis. Only a slight effect of controlled feeding was observed on the incidence of alveolar lipoproteinosis. Time-scheduled feeding did not cause a reduction in the incidence of tumours, but it delayed their occurrence. The risk to develop various types of tumours during the third year of life was significantly higher in the ad libitum group than in the rats fed by a controlled regime. The automaton Han:CHRONOFEEDER, used in this study, has proved to be an appropriate, relatively inexpensive and easily installable feeding system for automatic control of food accessibility. It is suitable to implement controlled feeding and food restriction of rodents in longterm experiments.

Five malignant mixed müllerian tumors and one rhabdomyosarcoma were observed in LEWIS rats. Heterologous müllerian neoplasms (cases 1-4) consisted of epithelial and mesenchymal elements including squamous epithelium, glandular epithelium and sarcomatous, rhabdomyosarcomatous, cartilaginous as well as osseous parts. All the heterologous tumors revealed undifferentiated areas with an anaplastic appearance. The homologous müllerian tumor (case 5) was composed of glandular epithelium embedded in sarcomatous tissue. The rhabdomyosarcoma (case 6) consisted of bundles of elongated strap-like cells mixed with cells resembling rhabdomyoblasts.

The occurrence of spastic paresis and paralysis in rats of the Han: WIST strain is described. The results of this study indicate that this neural disorder starts with progressive development at the age of about 4-5 weeks independent of the sex. At this time the affected animals are significantly smaller than the normal ones. The disease has been found to be due to an autosomal recessive gene. Electromyographic studies showed spontaneous discharges of tonic firing motor units.

In a long-term study, the life-expectancy of 320 female virgin Han:WIST rats was significantly lower than that of 320 male virgins, whereas no major differences existed in a successive study with retired breeders (296 females and 252 males) of the same stock. Within the sexes, the female retired breeders lived on average longer than the virgins, whereas the male retired breeders had a higher mortality between the 33rd and 36th month than their virgin counterparts. Differences in life-expectancy were mainly due to varying incidences of uterine adenocarcinomas in the females and an adverse development of pituitary gland tumors in the males. A sexual difference was found in both groups for tumors of the pituitary gland, the islet cells of the pancreas, mammary gland, subcutis and mesenteric lymph nodes. A possible hormonal influence on tumorigenesis is discussed.

A life-span study with 900 female virgin Han:NMRI mice (300 outbred controls, 300 of a fat subline and 300 of a lean subline) was carried out to determine the occurrence of spontaneous diseases with ad libitum or restricted feeding. Rare non-neoplastic lesions of the lungs (1-8%) were secondary inflammations, focal ossification and subintimal arterial 'plaques'. More frequent were age-dependent pulmonary mineralizations similar to psammoma bodies (3-18%) and crystal formations (4-22%). Food restriction did not affect the incidence of these lesions directly. Crystals were observed furthermore within infoldings of the tracheobronchial mucosa and intra- as well as extracellularly in the nasal cavities.

Efficiency of indirect immunofluorescence microscopy (IFM) for detection of M. pulmonis antibody (IgG) in rats was compared with results of enzyme-linked immunosorbent assay (ELISA), complement fixation (CF), cultural isolation and histopathology. IFM was carried out on M. pulmonis infected BHK-21 cells grown on cover slips or multitest slides. After acetone fixation these antigen carriers could be stored at -20 degrees C for several months so that serological tests could be done at any time and completed within 2 h. The IFM was strain specific and the sensitivity of the test was comparable with that of the ELISA, whereas the CF-test proved to be very insensitive. For routine monitoring, only in cases of fresh infections should time consuming cultural procedures be preferred to serological tests. Chronic disease stages were readily detected by histological examination.

Protein synthesis in cell-free systems of rat liver and kidney decreases markedly with age. Examination of activity changes of the different steps revealed for both types of organs that reduced binding of aminoacyl-tRNA to ribosomes and reduced peptidyl transfer might be of major importance for the decrease in overall protein synthesis whereas ageing has only little effect on translocation as well as on initiation and termination.

A life span study of 900 female virgin Han:NMRI mice (300 outbred controls, 300 of a fat subline, and 300 of a lean subline) was done to determine the occurrence of spontaneous disease with ad libitum or restricted feeding. Major nonneoplastic lesions in the glandular stomach were erosions, ulcers and adenomatous hyperplasia of the fundus. Ulcers, ranging in incidence with ad libitum feeding from 5 to 9% and with food restriction from 13 to 34%, either occurred secondary to other diseases or were due to stress associated with food restriction, causing death mainly in the lean subline. Adenomatous hyperplasia was most common in the control group (41%); the frequency increased with age and was significantly reduced by food restriction. The etiology of adenomatous gastric hyperplasia is yet unknown. However, a lack of antiparietal cell antibodies, as determined by an immunofluorescent technique, indicates that an autoimmune disorder is not involved and an increase in antral gastrin cells, as determined by avidin-biotin peroxidase immunocytochemistry, suggests a hormonal involvement in pathogenesis.

A variety of sex-dependent urinary proteins of low molecular weight, absent in females and in castrated males, can be identified in male rats by disc electrophoresis. In the urine of male rats of age 5.5 months, albumin comprises only 1-2% of the total protein. Albumin excretion increases greatly with age and associated kidney disease. Total protein excretion, however, stays the same or even decreases slightly as the rat ages, due to a loss of low molecular weight, sex-dependent, proteins. These are virtually absent in senescent rats (38 months of age), although total protein excretion rises tenfold in these animals due to high molecular weight plasma proteins passing into the urine; the glomerular filtration rate decreases to 70% of the value measured at 5.5 months of age.